2-benzyl-polycyclic guanine derivatives and process for preparing them

ABSTRACT

Antihypertensive and bronchodilating compounds of the formula or a pharmaceutically acceptable salt thereof, and a process for preparing them are disclosed, wherein: 
     R 1 , R 2 , R 3 , R a , R b  and R c  as defined in the disclosure; 
     pharmaceutical compositions containing said compounds; 
     methods of treatment using said compounds; and 
     a process for preparing polycyclic guanines comprising 
     a) reducing a nitrosopyrimidine, and treating the reduced nitrosopyrimidine with an acylating reagent to give the amidopyrimidine; 
     b) reacting the amidopyrimidine with a halogenating/cyclizing reagent to give a halopurine; 
     c) reacting, in the presence of a base, the halopurine with an amine to give the substituted aminopurine; and 
     d) closing the ring of the substituted aminopurine with a suitable dehydrating agent.

The present application is the United States national applicationcorresponding to International Application No. PCT/US 94/01728, filedFeb. 24, 1994 and designating the United States, which PCT applicationis in turn a continuation-in-part of U.S. application Ser. No.08/024599, filed Feb. 26, 1993 and 08/023549 filed Feb. 26, 1993 both ofwhich are now abandoned.

BACKGROUND

The present invention relates to 2-benzyl-polycyclic guanine derivativesuseful for treating cardiovascular and pulmonary disorders, as well asto their pharmaceutical compositions, methods for using the same and aprocess for preparing them. Most compounds of this invention weregenerically but not specifically disclosed in PCT publicationWO91/19717, published Dec. 26, 1991. We have found that the compounds ofthe present invention show unexpectedly superior cardiovascular andpulmonary activity compared to the compounds of the prior publication.

SUMMARY OF THE INVENTION

The present invention is directed to novel 2-benzyl-polycyclic guaninederivatives of the formula: ##STR1## or a pharmaceutically acceptablesalt thereof, wherein: R₁, R₂ and R₃ are independently selected from thegroup consisting of hydrogen, lower alkyl, lower alkoxy, halogeno,hydroxy, (di-lower alkyl)amino, 4-morpholinyl, 1-pyrrolidinyl,1-pyrrolyl, --CF₃, --OCF₃, phenyl and methoxyphenyl; or R₁ and R₂together are methylenedioxy; or R₁ and R₂ together with the carbon atomsto which they are attached form a benzene ring; and

R^(a) is hydrogen and R^(b) and R^(c), together with the carbon atoms towhich they are attached, form a saturated ring of 5 carbons; or R^(a) islower alkyl, R^(b) is hydrogen or lower alkyl, and R^(c) is hydrogen; orR^(a), R^(b) and the carbon atom to which they are attached form asaturated ring of 5-7 carbons, and R^(c) is hydrogen; or R^(a) ishydrogen, and R^(b), R^(c) and the carbon atoms to which they areattached form a tetrahydrofuran ring; or R^(a) and R^(b), together withthe carbon atom to which they are attached, and R^(b) and R^(c),together with the carbon atoms to which they are attached, each form asaturated ring of 5-7 carbons.

Preferred compounds are those wherein R₁ and R₃ are hydrogen. Morepreferred are compounds wherein R₁ and R₃ are hydrogen and R₂ ishydrogen, --OCF₃, methyl, methoxy, fluoro, phenyl, methoxyphenyl,dimethylamino, 1-pyrrolidinyl or 1-pyrrolyl, and compounds wherein R₁and R₂ together are methylenedioxy and R₃ is hydrogen.

Also preferred are compounds wherein R^(a) is hydrogen and R^(b) andR^(c), together with the carbon atoms to which they are attached, form asaturated ring of 5 carbons; compounds wherein R^(a) is lower alkyl,R^(b) is hydrogen or lower alkyl, and R^(c) is hydrogen; compoundswherein R^(a) and R^(b) and the carbon atom to which they are attachedform a saturated ring of 5 carbons and R^(c) is hydrogen; compoundswherein R^(a) is hydrogen and R^(b), R^(c) and the carbon atoms to whichthey are attached form a tetrahydrofuran ring; and compounds whereinR^(a) and R^(b), together with the carbon atoms to which they areattached, and R^(b) and R^(c), together with the carbon atoms to whichthey are attached, each form a saturated ring of 5 carbons. Morepreferred are compounds wherein R^(a) is hydrogen and R^(b) and R^(c),together with the carbon atoms to which they are attached, form asaturated ring of 5 carbons; compounds wherein R^(a) and R^(b) and thecarbon atom to which they are attached form a saturated ring of 5carbons and R^(c) is hydrogen; and compounds wherein R^(a) is loweralkyl, R^(b) is hydrogen or lower alkyl, and R^(c) is hydrogen.

Of compounds of formula I wherein R^(a) is hydrogen and R^(b) and R^(c),together with the carbon atoms to which they are attached, form asaturated ring of 5 carbons, most preferred are compounds wherein R₁, R₂and R₃ are as listed in the following table:

    ______________________________________    R.sub.1      R.sub.2      R.sub.3    ______________________________________    H            H            H    H            F            H    H            --OCH.sub.3  H    H            --CH.sub.3   H    H            (CH.sub.3).sub.2 N--                              H    H            C.sub.6 H.sub.5 --                              H    H            --OCF.sub.3  H                 1 #STR2##    H    H                 2 #STR3##    H    3,4-OCH.sub.2 O--    H    H            --C.sub.6 H.sub.4 OCH.sub.3                              H    ______________________________________

The compounds of formula I are useful as antihypertensive,bronchodilating and blood platelet inhibiting agents. Compounds of theinvention are useful in inhibiting phosphodiesterase enzymes; theinhibition of vascular phosphodiesterase is associated with vasodilationand vasorelaxation, and therefore is expected to induce antihypertensiveand antianginal activity. Compounds of formula I can also serve assmooth muscle relaxants and are therefore useful in the treatment ofbronchoconstriction. Such compounds also can inhibit smooth muscleproliferation, vascular growth and platelet function and are useful intreating conditions such as restenosis post angioplasty, atherosclerosisand conditions which benefit from inhibiting platelet function. Throughone or more of the above physiological mechanisms, compounds of formulaI are also useful in treating ischemia and peripheral vascular diseases.

The present invention is also directed toward a pharmaceuticalcomposition containing a compound of formula I in an amount effective toinhibit phosphodiesterase enzymes, smooth muscle proliferation, vasculargrowth or platelet function, or to relax smooth muscle. The presentinvention is also directed toward a pharmaceutical compositioncontaining an anti-hypertensive, an anti-anginal, a bronchodilating or aplatelet inhibiting effective amount of a compound of formula I.

The present invention is also directed toward a method for treatinghypertension, angina, bronchoconstriction, restenosis post angioplasty,atherosclerosis, ischemia, peripheral vascular diseases, or diseasesbenefitting from platelet inhibition in a mammal comprisingadministering to a mammal in need of such treatment an amount of acompound of formula I effective to treat any of the above diseases. Thepresent invention is also directed toward a method for maintainingguanosine 3':5'-cyclic monophosphate (cGMP) levels in a mammal byadministering an amount of a compound of formula I effective to maintainor increase cGMP levels.

In another embodiment, the present invention is directed toward thepreparation of a polycyclic guanine of formula II ##STR4## wherein, R⁴is H, alkyl or alkyl substituted with aryl or --OH;

R⁵ is H, halo, --CF₃, alkoxy, alkylthio, alkyl, cycloalkyl, --SO₂ NH₂,--NH₂, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino,--COOH, alkoxycarbonyl, aminocarbonyl, aryl, substituted aryl or alkylsubstituted with aryl, substituted aryl, --OH, alkoxy, --NH₂,monoalkylamino or dialkylamino;

R^(a1), R^(b1), R^(c1) and R^(d1) independently represent H, alkyl,cycloalkyl or aryl; or (R^(a1) and R^(b1)) or (R^(c1) and R^(d1)) or(R^(b1) and R^(c1)) can complete a saturated ring of 5- to 7- carbonatoms, or (R^(a1) and R^(b1)) taken together and (R^(b1) and R^(c1))taken together, each complete a saturated ring of 5- to 7-carbon atoms,wherein each ring optionally can contain a sulfur or oxygen atom andwhose carbon atoms may be optionally substituted with one or more or thefollowing: alkenyl, alkynyl, --OH, --COOH, alkoxycarbonyl, alkyl oralkyl substituted with --OH, --COOH or alkoxycarbonyl; or such saturatedring can have two adjacent carbon atoms which are shared with anadjoining aryl ring; and

n is zero or one;

wherein the process comprises:

a) reducing a nitrosopyrimidine (III), and treating the reducednitrosopyrimidine with an acylating reagent (IV), optionally in thepresence of either an acylating catalyst and/or coupling reagent and/orphase transfer catalyst to give the amidopyrimidine (V);

b) reacting the amidopyrimidine (V) with an effective amount of ahalogenating/cyclizing reagent, optionally in the presence of one ormore additional halide sources, and also optionally in the presence of aphase transfer catalyst to give a halopurine (VI);

c) reacting, in the presence of a base, the halopurine (VI) with anamine of the formula: ##STR5## wherein R^(a1), R^(b1), R^(c1), R^(d1)and n are as described above to give the substituted aminopurine (VIII);

d) closing the ring of the substituted aminopurine (VIII) with asuitable dehydrating agent to give the polycyclic guanine (II).

In another embodiment , the present invention is directed toward aprocess for preparing amidopyrimidines of formula V, comprising:reducing a nitrosopyrimidine of formula III, and treating the reducednitrosopyrimidine with an acylating reagent, optionally in the presenceof either an acylating catalyst and/or coupling reagent and/or phasetransfer catalyst. This process corresponds to step a) above.

In another embodiment, the present invention is directed toward aprocess for preparing a halopurine of formula VI, comprising reacting anamidopyrimidine (V) with an effective amount of a halogenating/cyclizingreagent, optionally in the presence of one or more additional halidesources, and also optionally in the presence of a phase transfercatalyst. This process corresponds to step (b) above. This process canfurther include step (c) and/or step (d), described below.

In another embodiment, the present invention is directed toward aprocess for preparing a substituted aminopurine of formula VIII,comprising reacting, in the presence of a base, the halopurine (VI) withan amine of the formula: ##STR6## wherein R^(a1), R^(b1), R^(c1), R^(d1)and n are as described above. This process corresponds to step c) above.This process can further comprise step (d), described below.

The present invention is also directed toward the novel intermediates:amidopyrimidine V, halopurine VI and aminopurine VIII, with the provisothat with regards to amidopyrimidine V, where Z is ═O, R⁴ and R⁵ cannotboth be methyl.

The present invention has the advantage of providing a process forpreparing polycylic guanine derivatives and intermediates thereof, in asfew or even fewer steps than other processes previously taught, in goodyields with little formation of undesirable by-products, with less wasteto dispose of or recycle. The present invention has the furtheradvantage of providing novel intermediates which enable the aboveprocess to achieve these advantages.

DETAILED DESCRIPTION OF THE INVENTION

In describing the present invention, "lower alkyl" represents a straightalkyl chain having from 1 to 6 carbon atoms or a branched alkyl chain of3 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl and hexyl.

"lower alkoxy" represents an alkoxy group wherein the alkyl portion isas defined above, for example, methoxy, ethoxy, propoxy, pentyloxy andhexyloxy.

"Halogeno" represents fluoro, chloro, bromo or iodo.

"Aryl" represents a carbocyclic moiety containing at least onebenzenoid-type ring, with the aryl moiety having from 6 to 14 carbonatoms, with all available substitutable carbon atoms of the aryl moietybeing intended as possible points of attachment, for example phenyl,naphthyl, indenyl, indanyl and the like.

"Substituted aryl" represents an aryl moiety as defined abovesubstituted with 1 to 3 substituents selected from the group consistingof halogeno, lower alkyl, --CF₃, --OCF3, phenyl, --OH, lower alkoxy,phenoxy, amino, (mono-lower alkyl)amino, (di-lower alkyl)amino,4-morpholinyl, 1-pyrrolidinyl, 1-pyrrolyl and methoxyphenyl, orsubstituents on adjacent carbon atoms form a methylenedioxy group.

Certain compounds of the invention e.g., those with a basic nitrogencontaining moiety, can also form pharmaceutically acceptable salts withorganic and inorganic acids. Examples of suitable acids for such saltformation are hydrochloric, sulfuric, phosphoric, acetic, citric,oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose skilled in the art. The salts are prepared by contacting the freebase form with a sufficient amount of the desired acid to produce a saltin the conventional manner.

Certain compounds of the invention will be acidic in nature, e.g., thosecompounds which possess a carboxy or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalts are the sodium, potassium, calcium, aluminum, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkylamines, hydroxyalkylamines,N-methylglucamine and the like.

Compounds of formula I form enantiomers, with the (+) enantiomeric formbeing preferred. For example, the preferred stereochemistry forcompounds wherein R^(a) is hydrogen and R^(b) and R^(c), together withthe carbon atoms to which they are attached, form a saturated ring of 5carbons is shown in the following partial structural formula: ##STR7##

The process aspect of the present invention and its various embodimentsare illustrated below: ##STR8## wherein R⁴, R⁵, R^(a1), R^(b1), R^(c1),R^(d1) and n are as defined above;

L is a leaving group;

X is halogeno;

Z is ═O or --OR⁶, wherein R⁶ is alkyl; and

the dotted lines "---" indicate an optional double bond such that when Zis ═O, position 1 contains hydrogen and there is single bond betweenpositions 1 and 2 on the ring, or when Z is --OR⁶ wherein R⁶ is alkyl,there is a double bond between positions 1 and 2 on the ring;

The amidopyrimidines of formula V can be prepared by reducing anitrosopyrimidines of formula III, followed by treatment with anacylating reagent. Suitable reducing agents include hydrogen with ametal catalyst, such as the metals from Group VIII of the periodic tableor salts or complexes thereof, or a mixture of metal of Group VIII withcarbon. Suitable metals include platinum, palladium, nickel, rhodium,ruthenium or mixtures thereof. The reduced nitrosopyrimidine is thentreated with an acylating reagent, optionally in the presence of eitheran acylating catalyst and or coupling reagent and/or phase transfercatalyst. In the reduction of nitrosopyrimidines, the metal catalyst canbe employed in amounts effective to give the reduced nitrosopyrimidine.Such amounts can range from about 1 to about 200 mole percent of themetal catalyst, preferably from about 1 to about 50 mole percent, morepreferably about 1 to about 20 mole percent metal catalyst. Reductioncan be carried out at temperatures effective to give the the reducednitrosopyrimidine, and can range from about -40° C. to about 100° C.,more preferably from about 0° to about 50° C., more preferably from 10°to 30° C. The nitrosopyrimidine of formula III is reduced underpressures ranging from about ambient to about 400 pounds per square inch(psi) (20 kilotorr), preferably from about 35 psi (1.8 kilotorr) to 100psi (5.1 kilotorr), more preferably from about 50 psi (2.6 kilotorr) to70 psi (3.6 kilotorr). The nitrosopyrimidine (III) can be reduced for atime sufficient to allow the desired completion of the reaction, such asfrom 10 minutes to one week or more, preferably from about 5 to 48hours.

Suitable acylating reagents include anhydrides, organic acid halides,mixed anhydrides, activated acid esters, organic acids or mixturesthereof of the formula R⁵ COL (IV) wherein R⁵ is as defined before, andL represents a leaving group, such as an anhydride, a halide or anactivated ester. Representative acylating reagents include acetic acid(HOAc), acetyl chloride, acetyl bromide, acetic anhydride, benzoylchloride, aryl substituted arylacetic acids or derivatives such aspara-trifluorophenylacetyl chloride, para-dimethylaminophenylacetylchloride and para-trifluorophenyl acid. Other acylating agents caninclude aryl substituted aryl acetic acid chlorides and anhydrides; orcan include acetic acid derivatives of formula 2 described in Route 1.The acylating reagents can be employed in amounts effective to acylatethe reduced nitrosopyrimidine, and can range from about 1 to about 10moles of acylating reagent per mole of reduced nitrosopyrimidine,preferably from about 1 to 4 moles of acylating reagent. Acylation canbe carried out at temperatures effective to give the amidopyrimidine(V), and can range from about -40° C. to about 50° C., more preferablyfrom about 0° to about 40° C. The acylation of the reducednitrosopyrimidine can be carried out at pressures ranging from aboutambient to about 400 pounds per square inch (psi) for a time sufficientto allow the desired completion of the reaction, such as from 10 minutesto 48 hours or more.

Suitable acylating catalysts include dimethylaniline,dimethylaminopyridine (DMAP) and imidazole. The acylating catalysts canbe employed in amounts effective to catalyze acylation of the reducednitrosopyrimidine. Such amounts can range from about 1 to about 20 molepercent acylating catalyst, preferably from about 1 to 10 mole percent.

Suitable coupling reagents include carbodiimides such asdicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC). Thelatter coupling reagent may incorporate its own catalyst(s), such asbenztriazoles, imidizoles, N-hydroxysuccinimides, and DMAP. The couplingreagent can be employed in an amount effective to aid acylation of thereduced nitrosopyrimidine. Such amounts can range from about 1 to about5 moles coupling reagent, preferably from about 1 to 4 moles.

The reduction and acylation steps can be carried out in a solventcompatible with the reactants. Such solvents include ethers, water,bases, acids, dimethylformamide (DMF) or mixtures thereof. Ethersinclude diethylether (Et₂ O), tetrahydrofuran (THF), tertiary butylmethyl ether ((CH₃)₃ COCH₃) and dimethoxyethane. Bases includehydroxides, carbonates or bicarbonates of alkali and alkaline earthmetals such as lithium, sodium, potassium, magnesium, calcium or barium.Preferably the base is in the aqueous form. Acids include compounds ofthe formula R⁵ COL (IV), wherein R⁵ is as defined hereinbefore, such asHOAc, propionic acid, butyric acid, or anhydrides of any of the aboveacids. Alternatively, the acids can include acidic acid derivatives offormula 2 described in Route 1. Mixtures of any of the above solventscan be employed. The amount of solvent should be sufficient to provide amixable slurry of the reactants.

Suitable phase transfer catalysts for promoting acylation in thepresence of aqueous or organic media of reduced nitrosopyrimidineinclude tetra-substituted phosphonium salts, quaternary ammonium salts,such as tetrabutylammonium, tetramethylammonium, benzyltributylammonium,with a complementary counterion such as sulfate, hydroxide or chloride.Suitable solvents for use with the phase transfer catalysts includealiphatic hydrocarbons such as C-5 to C-20 alkanes, including heptane,or aromatic hydrocarbons such as toluene, benzene and xylenes; andchlorinated hydrocarbons such as methylene chloride (CH₂ Cl₂),dichlorethane, chlorobenzene; or ethers such as described hereinbefore.

Amidopyrimidine V, wherein Z is ═O and R⁴ and R⁵ are both methyl isdescribed in A. Branfman et al., Drug Metabolism and Disposition,(1983), Vol. 11, pp. 206-210 and V. I. Khmelevskii et al. J. Gen. Chem.,U.S.S.R. (1958), Vol. 28, pp. 2016-2020.

The halopurine compound of formula VI can be prepared by reacting anamidopyrimidine (V) with an effective amount of a halogenating/cyclizingreagent, optionally in the presence of one or more additional halidesources, and also optionally in the presence of phase transfercatalysts. Suitable halogenating/cyclizing reagents include phosphoroustrihalide, a phosphorus pentahalide, organophosphorous halides, aphosphorus oxyhalide, thionyl halide, sulfuryl halide or mixturesthereof. The halogenating/cyclizing reagent can be employed in amountsranging from about equimolar to excess moles per mole ofamidopyrimidine, preferably from about one mole to about 50 moles of thehalogenating/cyclizing reagent. The reaction can be carried out attemperatures ranging from about ambient to the boiling point of thesolvent(s) employed, more preferably from about 50° C. to about 150° C.Also preferred is that the reactants are contacted at ambient pressures,although pressures greater than ambient can be employed. The reactantscan be reacted for a time sufficient to allow the desired completion ofthe reaction, such as from 10 minutes to about one week or more.

Suitable additional halide sources include ammonium halide such as NH₄Cl, NH₄ Br or NH₄ 1I, alkali metal halides such as LiCl, LiBr or LiI,halogen gases such as chlorine, bromine or iodine, and hydrogen halidessuch as HCl, HBr or HI. Such halide sources, together with thehalogenating/cyclizing reagent, can facilitate conversion ofamidopyrimidine (V) to halopurine (VI). The halide sources can beemployed in amounts ranging from about 0.1 moles to excess moles permole of amidopyrimidine, preferably from about 0.1 mole to about 5moles.

Suitable phase transfer catalysts for converting amidopyrimidine (V) tohalopurine (VI) can include those described for the above conversion ofthe reduced nitrosopyrimidine to amidopyrimidine. Such amounts can rangefrom about 0.1 to about 10 moles of phase transfer catalyst per mole ofamidopyrimidine, preferably from about 0.1 to about 5 moles.

The process for preparing halopurine VI can be carried out neat or withany solvent compatible with the reactants. Suitable solvents includealiphatic hydrocarbons such as C-5 to C-20 alkanes, preferably heptane,aromatic hydrocarbons such as toluene, benzene or xylenes, chlorinatedhydrocarbons such as CH₂ Cl₂, dichlorethane or chlorobenzenes, ormixtures of any of the above. Where the process is conducted neat, anexcess amount of the halogenating/cyclizing reagent can be employed. Theamount of solvent should be sufficient to provide a mixable slurry ofthe reactants.

The substituted aminopurine of formula VIII can be prepared by reactinghalopurine VI with a suitable amine, optionally in the presence of anadded base, optionally in the presence of phase transfer catalysts suchas those described for promoting acylation. Suitable amines can be thoseas described in PCT/US91/04154 of the formula: ##STR9## wherein R^(a1),R^(b1), R^(c1), R^(d1) and n are as defined above. Alternatively, thesalts of amines can be employed, such as the HCl salt. The amine can beemployed in amounts effective to give compound VIII, and can range fromabout equimolar to about 20 moles per mole of halopurine VI, preferablyfrom about one to about four moles of amine. Suitable added bases can beeither organic, inorganic or mixtures thereof. Organic bases can includenitrogen containing bases such as N-methylpyrrolidinone (NMP),triethylamine (Et₃ N), diisopropylethylamine (iPr₂ NEt), aniline,pyridine, 1,8-bis(dimethylamino)napthalene, polyvinyl pyridine, DMAP,dimethylaniline, leutidine, sodium tertiary butoxide and the like. Itshould be noted that the amine reactants described in PCT/US91/04154 canalso be employed as a base. Suitable inorganic bases can includehydroxide, carbonates and bicarbonates of alkali and alkaline earthmetals of Groups IA and IIA of the periodic table. Such bases caninclude NaOH, KOH, and sodium and potassium carbonates. The process canbe carried out at temperatures effective to give the substitutedaminopurine (VIII), and can range from about -20° C. to 200° C., morepreferably from about ambient about 150° C. Also preferred is that thereactants are contacted at ambient pressures, although pressures greaterthan ambient can be employed. Optionally, the process can be carried outin a solvent compatible with the reactants. Such solvents can includeany of the organic bases described above, acetonitrile (CH₃ CN), etherssuch as THF, (CH₃)₃ COCH₃, dimethoxyethane, amides such as DMF andacetamide, aliphatic hydrocarbons such as C-5 to C-20 alkanes andchlorinated hydrocarbons as described above, or mixtures of any of theabove solvents. The amount of solvent should be sufficient to provide amixable slurry of the reactants. Optionally, the process can be carriedout with phase-transfer agents, such as those defined hereinbefore.

The reactants can be contacted for a time sufficient to allow thedesired completion of the reaction, such as from one to 96 hours ormore, preferably from about 24 to about 72 hours.

The desired polycyclic guanine (II) can be prepared by known methods,such as those described in PCT/US91/04154. Generally, a substitutedaminopurine VIII can be converted to polycyclic guanine XI by ringclosure with a suitable dehydrating agent such as thionyl chloride(SOCl₂) or triphenylphosphine dibromide according to known procedures orprocedures analogous to known procedures.

Recovery of compounds II, V, VI and VIII from the reaction mixture canbe made using conventional recovery procedures, such as by extraction,crystallization, filtration and/or removal of any solvents present.

In addition to using the novel process described above, the compounds ofthe present invention can be prepared by several routes as describedhereinafter. Variations of these routes can be employed, as well asother routes known to those skilled in the art, such as those describedin WO91/19717, incorporated herein by reference.

For compounds of formula Ia wherein R^(a) is hydrogen and R^(b) andR^(c), together with the carbon atoms to which they are attached, form asaturated ring of 5 carbons, the following routes 1-3 can be used:##STR10##

Route 1, wherein R₁, R₂ and R₃ are as defined above, involves coupling auracil derivative of formula 1 with an acetic acid derivative of formula2 using standard peptide coupling techniques, e.g. using a couplingagent such as DEC and an activating agent such as DMAP in a suitableinert solvent such as DMF. The substituted uracil derivative of formulaa is then treated with a halide-forming agent such as POCl₃, and theresultant compound of formula 4 is aminated by reacting withtrans-2-hydroxycyclopentylamine (formula 5) at elevated temperatures(100-150° C.) in the presence of i-Pr₂ NEt in a solvent such as NMP. Theresultant compound of formula 6 is then treated with a dehydrating agentsuch as SOCl₂ to form the polycyclic ring structure of formula 7.Compounds of formula I can then be obtained by removing theamino-protecting benzyl group, e.g. by hydrogenation with a suitablepalladium catalyst and hydrogen or HCO₂ NH₄.

Starting uracil derivatives of formula 1 can be prepared by methodsknown in the art, for example by methods disclosed in WO91/19717. Theaminoalcohol of formula 5 can be prepared by methods known in the artand by the following procedure: ##STR11## wherein Bn is benzyl. In thereaction scheme, cyclopentene oxide (8) is converted to thecorresponding N-benzyl trans-hydroxycycloalkylamine of formula 9 byrefluxing with benzyl amine, and the benzyl protecting group is theremoved, e.g. by hydrogenation, to obtain thetranshydroxycycloalkylamine of formula 5. ##STR12##

In Route 2, the known starting tetracycle of formula 10 is reacted witha base such as lithiumdiisopropylamide (LDA) in a suitable solvent suchas THF, then with a benzaldehyde of formula 11. The resultant compoundof formula 12 is then reduced, for example by hydrogenation withpalladium catalyst and hydrogen in the presence of HCl to obtain acompound of formula Ia. ##STR13##

In Route 3, the known starting material of formula 13 is brominated, forexample by reaction with a mixture of bromine and sodium acetate inHOAc. The reagent of formula 16 is prepared by treating with zinc abromomethyl aryl compound of formula 15 (wherein Ar is optionallysubstituted phenyl or naphthyl). The reagent of formula 16 is thenreacted with the compound of formula 14 in the presence of a catalystsuch as tetrakis-(triphenylphosphine)palladium (Pd(PPh₃)₄) andtriphenylphosphine (PPh3) in the presence of a polar solvent such as NMPunder an inert atmosphere.

Other compounds of formula I can be prepared by the following routes4-6: ##STR14##

Route 4, wherein R₁, R₂ and R₃ are as defined above, involves reacting asubstituted imidazole carboxylate of formula 17 with CH₃ NCO in thepresence of a base such as pyridine. The resultant compound of formula18 is then heated with an aqueous base such as NaOH to form the bicycliccompound of formula 19, which is then treated with a halide-formingagent such as POCl₃ to obtain a compound of formula VIa (i.e., acompound of formula VI wherein R⁴ is methyl, X is chloro and R⁵ isoptionally substituted benzyl). Compounds of formula VIa are treated asdescribed in the claimed process to obtain compounds of formula I.##STR15##

The first step in-Route 5 involves reacting an amino alcohol of formulaVII with a chloropurine of formula 20 under the same conditions as stepc of the claimed process to obtain a compound of formula 21. Usingprocedures described in Routes 1 and 2, compounds of formula I can bedehydrated with SOCl₂ or triphenylphosphine dibromide to form apolycyclic compound, which is then reacted with a base such as LDA in adry solvent such as THF at low temperature, treated with an electrophilesuch as an aryl aldehyde of formula 11 and hydrogenated to givecompounds of formula I.

Compounds of formula Ib wherein R^(a) is hydrogen and R^(b) and R^(c)complete a tetrahydrofuran ring are prepared by the following procedure:##STR16##

In the above procedure, a chloropurine of formula 4 is reacted atelevated temperature with an amino alcohol of formula 22 in the presenceof a base such as Et₃ N and in a solvent such as NMP, and the resultantintermediate product is then reacted with CH₃ SO₂ Cl in the presence ofa base such as Et₃ N to obtain an intermediate of formula 23. Theintermediate of formula 23 is then subjected to hydrogenolysis, forexample by treatment with NH₄ HCO₂ and a palladium catalyst, to obtain acompound of formula Ib.

Intermediate amino alcohols of formula 22 can be prepared by methodsknown in the art, for example by the following procedure: ##STR17##wherein 1,4-dihydrofuran is reacted with m-chloroperoxybenzoic acid(m-CPBA) to obtain the compound of formula 24, which is then reactedwith R-(+)-α-methylbenzylamine to give the substituted amino alcohol offormula 25. The diastereomeric intermediates of formula 25 are separatedat this stage by recrystallization from CH₂ Cl₂ and hexane. Compound 25is then hydrogenated by refluxing with NH₄ HCO₂ in CH₃ OH over Pd/C togive the trans-substituted aminoalcohol of formula 22.

Starting materials of formulae 1, 2, 5, 8, 10, 11, 13, 15 and 17 arereadily available or can be prepared by methods well known in the art.

The following examples are presented to illustrate typical intermediatecompounds of the present invention, but the scope of the invention isnot to be considered limited to such examples. In the formulae, Me ismethyl.

PREPARATION 1N-(6-Amino-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-pyrimidinyl)acetamide ##STR18## Method 1: Hydrogenate overnight, in a parr shaker, amixture of 100 g of 6-amino-3-methyl-5-nitroso-2,4(1H,3H)-pyrimidinedione and 20 g of 5% Pd/C catalyst in 1.0 L of glacialHOAc. Filter the reaction mixture through 10 g of a diatomaceous earthknown as celite®, trademark of the Johns-Manville Products Corporation,Celite Division, Manville, N.J. Wash the celite cake with 125 mL ofglacial HOAc and save the cake. Add 45 mL of acetic anhydride along withoptionally, a trace of DMAP as a catalyst to the filtrate. Stir themixture overnight at 40° C. and then concentrate to dryness undervacuum. Add 125 mL of water to the resultant solid and stir the mixtureat 0° C. in an ice-water bath for 1 hour. Filter the resultant solid anddry in a draft oven at 40-50° C. to obtain 26.3 g of product. Extractthe celite cake with eight 250 mL portions of hot HOAc. Concentrate theextracts to obtain a tan solid, slurry in 300 mL water and then treat asdescribed above to give 85.4 g of product. Combining the solids gives111.7 g (95% crude yield) of the title compound. Recrystallize a samplefrom hot CH₃ OH/HOAc/C to give the purified title compound as a whitesolid, melting point (m.p.) greater (>) than 250° C. MS (El): 198 (M+).

Method 2: Hydrogenate overnight, in a parr shaker, a suspension of 1 gof 6-amino-3-methyl-5-nitroso-2,4(1H, 3H)-pyrimidinedione and 0.1 g 5%Pd/C catalyst in 12.2 mL of 1N NaOH. Filter the catalyst, wash with asmall amount of 1N NaOH, cool the filtrate to 0° C., stir and add 2 mLof acetic anhydride. Stir for two hours while allowing the reactionmixture to warm to room temperature, filter, wash with water followed byhexanes and dry overnight in a draft oven at 45° C. to obtain 0.82 g(70% yield ) of title compound, a light tan solid.

PREPARATION 2N-(6-Amino-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-pyrimidinyl)phenylacetamide ##STR19## In a parr shaker, hydrogenate overnight asuspension of 1 g of 6-amino-3-methyl-5-nitroso-2,4(1H,3H)-pyrimidinedione and 0.1 g of 5% Pd/C catalyst in 6.2 mL of 1N NaOH.Filter the catalyst, wash with a small amount of 1N NaOH, cool thefiltrate to 0° C., stir and add 0.75 mL of benzoyl chloride. Stir for 1hr, filter (save the filtrate), wash the product with water followed byhexanes and dry in a draft oven at 45° C. to obtain 1.06 g of product asa light yellow solid. The filtrate is stirred at 0° C. and 0.375 mLbenzoyl chloride is added. From this, 0.31 g of product is collected asabove, to give 1.36 g (89% total yield) of title compound, MS (Cl/CH₄):261 (M+H) m.p.>250° C. PREPARATION 3 N-(4-Amino-1,6dihydro-2-methoxy-1-methyl-6-oxo-5-pyrimidinyl)acetamide ##STR20## In aparr shaker, hydrogenate overnight a mixture of 4.5 g of6-amino-2-methoxy-3-methyl-5-nitroso-4(3H)-pyrimidinedione and 0.45 g of5% Pd/C catalyst in 45 mL of glacial HOAc. Filter the reaction mixturethrough 1.1 g celite. Wash the celite cake with 1.2 mL glacial HOAc. Tothe filtrate add 2.8 mL acetic anhydride, and optionally, a trace ofDMAP as a catalyst. Stir the mixture 1 hour at room temperature and thenfilter to collect first crop (0.86 g) of product. Concentrate the motherliquor and filter to collect additional 2.5 g of product. Finally,concentrate the mother liquor to obtain 1.2 g of additional product, togive a total of 4.56 g (90% yield) of the title compound a light tansolid. MS: (FAB) 213 (M+H). PREPARATION 3.1N-(6-Amino-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-pyrimidinyl)-4-(trifluoromethyl)benzeneacetamide##STR21## Hydrogenate, in a Parr shaker, a suspension of 2.3 g of6-amino-3-methyl-5-nitroso-2,4(1H, 3H)-pyrimidinedione and 0.23 g 5%Pd/C in 13 ml 1N NaOH overnight. Filter the catalyst, wash with a smallamount of 1N NaOH, cool the filtrate to 0° C., stir and add 4.6 g ofp-trifluoromethyl phenyl acetyl chloride. Stir for two hours whileallowing it to attain room temperature, filter, wash with water followedby hexanes, and dry overnight in a draft oven (45° C.) to obtain 5.2 gof the title compound, a light tan solid. Suspend this solid in CH2Cl2,stir for 1 h, filter and dry to obtain 4.0 g (87%) of the title compoundas an off-white solid, suitable for further reactions, m.p.>300° C. MS(El): 342 (M+), Cl (CH₄): 343 (M+H). PREPARATION 42-Chloro-1,7-dihydro-1,8-dimethyl-6H-purine-6-one ##STR22## Method 1:Reflux a suspension of 20 g the product of Preparation 1 in 300 mL ofPOCl₃ for 2-4 days, until the reaction is completed as determined bythin-layer chromatography (TLC). Remove POCl₃ under reduced pressure andadd a small amount of ice cold water to the resultant dark gummy solid.Stir this mixture vigorously and then bring to a neutral pH at 0°-5° C.by a slow addition of ice cold NH₄ OH. Filter the resultant orange-tansolid, wash with a small amount of ice cold water and dry in a draftoven at 40° C. to give 16.5 g (crude yield 82%) of the title compound.MS (Cl/CH4)199:201 in ˜3:1 ratio (M+H), m.p.>250° C.

Method 2: Reflux a mixture of 2 g of the product of Preparation 1 and0.76 g of NH₄ Cl in 30 mL of POCl₃ gently for 1-2 days, until thereaction is completed as determined by TLC. Remove POCl₃ under reducedpressure and add a small amount of ice cold water to the resultant gum.Stir this mixture vigorously and then bring to neutral pH at 0°-5° C. bya slow addition of ice cold NH₄ OH. Filter the resultant orange-tansolid, wash with a small amount of ice cold water and dry in a draftoven at 40° C. to give 1.7 g (crude yield 83.5%) of the title compound.

Method 3: Reflux a suspension of 0.55 g the product of Preparation 3 in12 mL of POCl₃ gently for 2-4 days, until the reaction is completed asdetermined by TLC. Remove POCl₃ and neutralize as described in Method 1.Filter the resultant light brown solid product and dry in a draft ovenat 40° C. to obtain 0.3 g of product. Extract the mother liquor withethyl acetate, dry the organic layer over anhydrous Na₂ SO₄ andconcentrate under reduced pressure to obtain 0.05 g of additionalproduct. Finally concentrate the mother liquor to dryness, extract with10% methanol in ethylacetate (EtOAc), filter and remove the solvents toobtain additional 0.56 g of product, to give a total of 0.41 g(80%yield) of the title compound.

PREPARATION4.1 2-Chloro-1,7-dihydro-1-methyl-8-(4-trifluoromethyl)phenyl!methyl!-6H-purin-6-one ##STR23## Heat amixture of 5 g ofN-(6-Amino-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-pyrimidinyl)-(4'-trifluoromethyl)phenylacetamideand 1.25 g NH₄ Cl in 75 ml POCl₃ at 70° for 24 h (until consumption ofthe starting material as judged by tlc). Gently reflux (˜110° C.) thereaction mixture for 3 days. Remove POCl₃ under reduced pressure. Add asmall amount of ice cold CH₂ Cl₂ to the resultant gum. Stir this mixturevigorously, then bring to a pH of 9-10 at 0°-5° C. by a slow addition ofice cold NH₄ OH. Remove CH₂ Cl₂, add a small amount of water (and NH₄ OHif needed to maintain neutral to alkaline pH), filter the resultant darkbrown solid, wash with a small amount of ice cold water and dry in adraft oven at 40° C. to obtain 5.3 g of the title compound. Slurry thisin CH₂ Cl₂, filter and dry to obtain 4.6 g (90% mass balance) of thetitle compound, a light brown solid, suitable for further reactions. MS(Cl/CH₄) 343:345 (M+H) in ˜3:1 ratio; El 342:344 (M+) in ˜3:1 ratio.PREPARATION 5 1,7-Dihydro-2-(2R-hydroxy-R-cyclopentyl)amino!-1,8-dimethyl-6H-purin-6-one ##STR24##Reflux a mixture of 12.5 g of the product of Preparation 4, 8 g of2R-hydroxy-R-cyclopentyl amine, and 31.5 mL of Et₃ N in 83 mL of CH₃ CNfor 2-3 days, until the reaction is completed as determined by TLC.Remove the volatiles in the reaction mixture under vacuum and then treatwith ice cold water. Stir this suspension at 0-5° C. and filter. Washthe solid with ice cold water and dry in a draft oven at 40° C. to give14.4 g (crude yield 87%) of the title compound, a light brown solid.m.p. 235-245° C. (decomposition) MS (Cl/CH₄) 264 (M+H); El 263. Thiscompound can be converted to a 2-methyl-polycyclic guanine derivative byemploying ring closure procedures described herein or in WO 91/19717.PREPARATION 5.1 1,7-Dihydro-2-(2R-hydroxy-R-cyclopentyl)amino!-1-methyl-8- (4-(trifluoromethyl)phenyl!methyl!-6H-purin-6-one ##STR25## Reflux (˜110° C.) a mixture of90 g of the product of Preparation 4.1, 36.3 g of2R-hydroxy-R-cyclopentyl amine, and 151 ml iPr₂ NEt (Hunig's base) in151 ml NMP for 24 h (until complete reaction as judged by tlc). Allow toattain room temperature, add 1 L ice cold water, stir vigorously for 1 hand then pour this in 3.5 L water. Stir for 1 8 h, filter and dry in adraft oven at 40° C. to obtain 87 g (81% mass balance) of the titlecompound, a light tan solid, suitable for further reaction. MS (Cl/CH₄)408 (M+H); El 407 (M); m.p. 285° C. (decomposition).

The following exemplify preparation of the 2-benzyl-polycylic guaninederivatives.

EXAMPLE 1 ##STR26## Step 1: Dissolve6-amino-3-methyl-5-(phenylmethylamino)pyrimidine-2,4-dione (12.3 g),phenylacetic acid (6.80 g), DEC (9.55 g) and DMAP (1.0 g) in dry DMF andstir the reaction mixture overnight at room temperature. Pour thereaction mixture onto ice, filter the product and wash with Et₂ O toobtain: ##STR27##

Using appropriate starting materials and essentially the same procedure,the following compounds can also be prepared:

    __________________________________________________________________________    1.1a                      .sup.1 H NMR(DMSO, 300 MHz)δ 3.00(3H, s,    3 #STR28##                NCH.sub.3), 3.48(2H, bs, COCH.sub.2), 4.55(2H,                              AB, J.sub.A,B =14.00Hz, NCH.sub.2), 6.25(2H,                              bs, NH.sub.2), 7.0-7.50(9H, m, C.sub.6 H.sub.5                              and C.sub.6 H.sub.4)    1.1b                      .sup.1 H NMR(DMSO, 200 MHz)δ 3.00(3H, s,    4 #STR29##                 NCH.sub.3), 3.35(2H, bs, COCH.sub.2), 3.70(3H,                              s, OCH.sub.3), 4.52(2H, AB, J.sub.A,B =15.00Hz,                              NCH.sub.2), 6.18(2H, bs, NH.sub.2), 6.8 and                              7.05 (4H, 2d, C.sub.6 H.sub.4 OMe),                              7.2-7.40(5H, m, C.sub.6 H.sub.5)    1.1c                      .sup.1 H NMR(DMSO, 300 MHz)δ 3.00(3H, s,    5 #STR30##                 NCH.sub.3), 3.60(2H, bs, COCH.sub.2), 4.55(2H,                              AB, J.sub.A,B =15.00Hz, NCH.sub.2), 6.30(2H,                              bs, NH.sub.2), 7.10-7.50(7H, m, C.sub.6 H.sub.5                              and C.sub.6 H.sub.4 CF.sub.3), 7.70(2H, d,                              C.sub.6 H.sub.4 CF.sub.3)    1.1d                      .sup.1 H NMR(DMSO, 200 MHz)δ 2.88(6H, s,    6 #STR31##                 N(CH.sub.3).sub.2), 3.05(3H, s, NCH.sub.3),                              3.35(2H, bs, COCH.sub.2), 4.58(2H, AB,                              J.sub.A,B =14.00Hz, NCH.sub.2), 6.18(2H, bs,                              NH.sub.2), 6.65 and 6.96 (4H, 2d, J=8.65,                              C.sub.6 H.sub.4 NMe.sub.2), 7.25(5H, m, C.sub.6                              H.sub.5)    1.1e                      .sup.1 H NMR(DMSO, 200 MHz)δ 3.15(3H, s,    7 #STR32##                 NCH.sub.3), 3.95(2H, bs, COCH.sub.2), 3.60(3H,                              s, OCH.sub.3), 3.80(6H, s, 2OCH.sub.3),                              4.60(2H, AB, J.sub.A,B =15.00Hz, NCH.sub.2),                              6.18(2H, bs, NH.sub.2), 6.50(2H, s C.sub.6                              H.sub.2 (OMe).sub.3), 7.2-7.50 (5H, m, C.sub.6                              H.sub.5)    1.1f                      .sup.1 H NMR(DMSO, 200 MHz)δ 3.10(3H, s,    8 #STR33##                 NCH.sub.3), 4.20(2H, bs, COCH.sub.2), 3.70(6H,                              s, 2OCH.sub.3), 4.50(2H, AB, J.sub.A,B =16.00Hz,                               NCH.sub.2), 6.10(2H, bs, NH.sub.2), 6.80(3H, m                              C.sub.6 H.sub.3 (OMe).sub.2), 7.2-7.50(5H, m,                              C.sub.6 H.sub.5)    __________________________________________________________________________

Step 2: Dissolve compound 1.1 (5.0 g) in 150 mL of POCI₃ and reflux for8 h. Cool the reaction mixture and pour into 300 mL of hexane. Let thereaction mixture stand for 0.5 h. Decant the solvent, cool the remainingresidue, adjust to pH 8 with 3 N NaOH, extract with 3×200 mL of CH₂ Cl₂,dry and evaporate the solvent. Column chromatograph the residue (2:98MeOH:CH₂ Cl₂) to obtain the product.

    __________________________________________________________________________    1.2                  .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ 3.80(3H,                         s,    9 #STR34##           NCH.sub.3), 4.30(2H, s, CH.sub.2 Ph), 5.50(2H, s,                         NCH.sub.2 Ph), 7.35(10H, m, 2C.sub.6 H.sub.5)    __________________________________________________________________________

Using appropriate starting materials and essentially the same procedure,following compounds can also be prepared:

    __________________________________________________________________________    1.2a                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             3.75(3H, s,    0 #STR35##               NCH.sub.3), 4.10(2H, s, CH.sub.2 PhF), 5.50(2H,                             s, NCH.sub.2), 6.90-7.20 and 7.30(9H, 2m,                             C.sub.6 H.sub.4 F and C.sub.6 H.sub.5)    1.2b                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             3.70(3H, s,    1 #STR36##                NCH.sub.3), 3.80(3H, s, OCH.sub.3), 4.05(2H, s,                             CH.sub.2 PhOMe), 5.50(2H, s, NCH.sub.2 Ph), 6.80                             (2H, d, J=8.50Hz, C.sub.6 H.sub.4 OMe), 7.0-7.10                             and 7.30(7H, 2m, C.sub.6 H.sub.4 OMe and C.sub.6                             H.sub.5)    1.2c                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             3.75(3H, s,    2 #STR37##                NCH.sub.3), 4.18(2H, s, CH.sub.2 PhCF.sub.3),                             5.55(2H, s, NCH.sub.2 Ph), 7.00(2H, m, C.sub.6                             H.sub.4 CF.sub.3), 7.20- 7.40(5H, m, C.sub.6                             H.sub.5), 7.50(2H, d, J=8.20 Hz, C.sub.6 H.sub.4                             CF.sub.3)    1.2d                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             2.90(6H, s,    3 #STR38##               N(CH.sub.3).sub.2), 3.70(3H, s, NCH.sub.3),                             4.05(2H, s, CH.sub.2 PhNMe.sub.2), 5.45(2H, s,                             NCH.sub.2 Ph), 7.0 (2H, d, C.sub.6 H.sub.4                             NMe.sub.2), 7.0-7.10 and 7.30 (7H, m, C.sub.6                             H.sub.4 NMe.sub.2 and C.sub.6 H.sub.5)    1.2e                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             3.35(3H, s,    4 #STR39##               NCH.sub.3), 3.60(3H, s, OCH.sub.3), 3.65(6H, s,                             2OCH.sub.3), 4.15(2H, s, CH.sub.2 Ph(OMe).sub.3),                              5.70 (2H, s, NCH.sub.2 Ph), 6.45(2H, s, C.sub.6                             H.sub.2 -- (OMe).sub.3), 7.10 and 7.30(5H, 2m,                             C.sub.6 H.sub.5)    1.2f                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             3.72(3H, s,    5 #STR40##                NCH.sub.3), 3.78 and 3.85(6H, 2s, 2OCH.sub.3),                             4.08(2H, s, CH.sub.2 Ph(OMe).sub.2), 5.50(2H, s,                             NCH.sub.2 Ph), 6.70(3H, m, C.sub.6 H.sub.3),                             7.05 and 7.30(5H, 2m, C.sub.6 H.sub.5)    __________________________________________________________________________

Suspend compound 1.2 (2.70 g), trans-2-hydroxycyclopentylamine (1.40 g)and i-Pr₂ NEt (5.20 mL) in 10 mL of NMP and seal the reaction vessel.Keep the mixture at 120-125° C. for 6-8 h. Cool the reaction mixture,add 20 mL of ice water and filter the precipitate with cold water anddry to obtain the product:

    __________________________________________________________________________    1.3                       .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                              1.40-2.20    6 #STR41##                 (6H, m), 3.38(3H, s, NCH.sub.3), 4.00(2H, s,                              CH.sub.2 Ph), 4.10(2H, m), 5.50(2H, AB,                              J.sub.A,B =14.0Hz, NCH.sub.2 Ph),                              7.20-7.30(10H, m, C.sub.6 H.sub.5)    __________________________________________________________________________

Using appropriate starting materials and essentially teh same procedure,the following compounds can also be prepared:

    __________________________________________________________________________    1.3a                      .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                              1.40-2.30    7 #STR42##                 (6H, m), 3.40(3H, s, NCH.sub.3), 4.00(2H, s,                              CH.sub.2 PhF), 4.10(2H, m), 5.40(2H, AB,                              J.sub.A,B =14.0Hz, NCH.sub.2 Ph), 7.20 and 7.30                              (9H, 2m, C.sub.6 H.sub.5 and C.sub.6 H.sub.4                              F)    1.3b                      .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                              1.45-2.30    8 #STR43##                 (6H, m), 3.40(3H, s, NCH.sub.3), 3.75(3H, s,                              OCH.sub.3), 4.00(2H, s, CH.sub.2 PhOMe), 4.10                              (2H, m), 4.75(1H, d, J=1.80Hz), 5.45(2H, AB,                              J.sub.A,B =14.0Hz, NCH.sub.2 Ph), 6.88 and                              7.05(4H, 2d, J=8.0Hz, C.sub.6 H.sub.4 OMe),                              7.05 and 7.30(5H, 2m, C.sub.6 H.sub.5)    1.3c                      .sup.1 H NMR(CDCl.sub.3, 300 MHz)δ                              1.50-2.40    9 #STR44##                 (6H, m), 3.48(3H, s, NCH.sub.3), 4.15(2H, s,                              CH.sub.2 PhCF.sub.3), 4.10(2H, m), 4.68(1H, d,                              J=1.80Hz), 5.50(2H,AB, J.sub.A,B =14.0Hz,                              NCH.sub.2 Ph), 7.05(2H, dd, J=8.0 and 1.80 Hz,                              C.sub.6 H.sub.4 CF.sub.3), 7.27(5H, m, C.sub.6                              H.sub.5), 7.51 (2H, d, J=8.0Hz, C.sub.6 H.sub.4                              CF.sub.3)    1.3d                      .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                              1.40-2.40    0 #STR45##                 (6H, m), 2.90(6H, s, N(CH.sub.3).sub.2),                              3.40(3H, s, NCH.sub.3), 3.95(2H, s, CH.sub.2                              PhNMe.sub.2), 4.05 (2H, m), 4.80(1H, d,                              J=2.0Hz), 5.45(2H, AB, J.sub.A,B =15.0Hz,                              NCH.sub.2 Ph), 6.65 and 7.05(4H, 2d, J=8.0Hz,                              C.sub.6 H.sub.4 NMe.sub.2), 7.10 and 7.30(5H,                              2m, C.sub.6 H.sub.5)    1.3e                      .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                              1.45-2.20    1 #STR46##                 (6H, m), 3.40(3H, s, NCH.sub.3), 3.75(6H, s,                              2OCH.sub.3), 3.85(3H, s, OCH.sub.3), 4.00(2H,                              s, CH.sub.2 Ph(OMe).sub.3), 4.10(2H, m),                              5.50(2H, AB, J.sub.A,B =14.50Hz, NCH.sub.2 Ph),                              6.35(2H, s, C.sub.6 H.sub.4 (OMe).sub.3), 7.05                              and 7.30(5H, 2m, C.sub.6 H.sub.5)    1.3f                      .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                              1.45-2.30    2 #STR47##                 (6H, m), 3.45(3H, s, NCH.sub.3), 3.78 and 3.85                              (6H, 2s, 2OCH.sub.3), 4.05(2H, s, CH.sub.2 Ph--                              (OMe).sub.2), 4.10(2H, m), 5.45(2H, AB,                              J.sub.A,B =15.0Hz, NCH.sub.2 Ph), 6.75(3H, 2d,                              C.sub.6 H.sub.4 (OMe).sub.2), 7.05 and 7.28(5H,                              2m, C.sub.6 H.sub.5)    __________________________________________________________________________

Step 4: Add 2.30 g of SOCl₂ (19.35 mmol) to a solution of compound 1.3(2.75 g, 6.45 mmol) in CH₂ Cl₂ and stir the reaction mixture overnight.Wash the reaction mixture with cold 2 N NaOH, dry and evaporate thesolvent. Chromatograph the residue on silica, eluting with CH₂ Cl₂ /CH₃OH (98:2) to give the product:

    __________________________________________________________________________    1.4                   .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ 1.45-2.05    3 #STR48##             (5H, m), 2.20(1H, dd), 3.40(3H, s, NCH.sub.3),                          3.98(2H, s, CH.sub.2 Ph), 4.75(1H, t) 4.90(1H, t),                          5.50(2H, s, NCH.sub.2 Ph), 7.10 and 7.30 (10H, 2m,                          C.sub.6 H.sub.5)    __________________________________________________________________________

Using appropriate starting materials and essentially the same procedure,the following compounds can also be prepared:

    __________________________________________________________________________    1.4a                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             1.50-2.10    4 #STR49##                (5H, m), 2.30(1H, dd), 3.40(3H, s, NCH.sub.3),                             4.00(2H, s, CH.sub.2 PhF), 4.80(1H, t) 4.92(1H,                             t), 5.42(2H, s, NCH.sub.2 Ph), 7.10 and 7.32(9H,                             2m, C.sub.6 H.sub.5 and C.sub.6 H.sub.4 F)    1.4b                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             1.50-2.00    5 #STR50##                (5H, m), 2.28(1H, dd), 3.35(3H, s, NCH.sub.3),                             3.80(3H, s, OCH.sub.3), 3.98(2H, s, CH.sub.2                             PhOMe), 4.75(1H, t) 4.85(1H, t), 5.35(2H, s,                             NCH.sub.2 Ph), 6.80 and 7.05 (4H, 2d, J=8.0Hz,                             C.sub.6 H.sub.4 OMe), 7.10 and 7.30(5H, 2m,                             C.sub.6 H.sub.5)    1.4c                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             1.50-2.10    6 #STR51##                (5H, m), 2.28(1H, dd), 3.38(3H, s, NCH.sub.3),                             4.08(2H, s, CH.sub.2 PhCF.sub.3), 4.78 (1H, t),                             4.90(1H, t), 5.40(2H, s, NCH.sub.2 Ph), 7.05(2H,                             dd, J=8.0 and 1.80 Hz, C.sub.6 H.sub.5) ,                             7.30(3H, m, C.sub.6 H.sub.5), 7.20 and 7.50(4H,                             2d, J=8.0Hz, C.sub.6 H.sub.4 CF.sub.3)    1.4d                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             1.50-2.00    7 #STR52##               (5H, m), 2.30(1H, dd), 2.90(6H, s,                             N(CH.sub.3).sub.2), 3.30(3H, s, NCH.sub.3),                             3.92(2H, CH.sub.2 PhNMe.sub.2), 4.72(1H, t),                             4.88(1H, t), 5.35(2H, s, NCH.sub.2 Ph), 6.65 and                             7.00 (4H, 2d, J=8.0Hz, C.sub.6 H.sub.4 NMe.sub.2)                             , 7.12 and 7.30(5H, 2m, C.sub.6 H.sub.5)    1.4e                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             1.50-2.00    8 #STR53##                (5H, m), 2.25(1H, dd), 3.35(3H, s, NCH.sub.3),                             3.70(6H, s, 2OCH.sub.3), 3.80(3H, s, OCH.sub.3),                             3.95(2H, s, CH.sub.2 Ph(OMe)3), 4.75 (1H, t)                             4.90(1H, t), 5.40(2H, s, NCH.sub.2 Ph), 6.30(2H,                             s, C.sub.6 H.sub.4 (OMe).sub.3), 7.10 and 7.30                             (5H, 2m, C.sub.6 H.sub.5)    1.4f                     .sup.1 H NMR(CDCl.sub.3, 200 MHz)δ                             1.50-2.00    9 #STR54##                (5H, m), 2.40(1H, dd), 3.40(3H, s, NCH.sub.3),                             3.78(6H.s. 2OCH.sub.3), 3.85(3H, s, OCH.sub.3),                             4.10(2H, s, CH.sub.2 Ph(OMe).sub.2), 4.75 (1H,                             t) 4.85(1H, t), 5.50(2H, s, NCH.sub.2 Ph), 6.80                             and 6.62(3H, 2m, C.sub.6 H.sub.4 (OMe).sub.2),                             7.10 and 7.30(5H, 2m, C.sub.6 H.sub.5)    __________________________________________________________________________

Step 5: Suspend compound 1.4 (4.00 g) and 10% Pd/C (4.00 g) in 100 mL ofCH₃ OH, add NH₄ HCO₂ and reflux for 6 h. Cool the reaction mixture,filter and evaporate the solvent. Add 20 mL of water to the resultantresidue, adjust to pH to 8, extract with CH₂ Cl₂, dry and evaporate thesolvent to produce the title compound (1): ¹ H NMR (CDCl₃ +drop of CD₃OD, 200 MHz) δ 1.50 (1 H, m), 1.65-2.00(5 H, m),2.28 (1 H, J═7.50 &12.50 Hz), 3.28 (3 H, s, NCH₃), 4.18 (2 H, s, CH₂ Ph), 4.75(1 H, t,J═7.00 Hz), 4.90 (1 H, t, J═7.00 Hz), 7.30 (5 H, m, C₆ C₅).

Using the same procedure, hydrogenate compounds 1.4a to 1.4c of Step 4to obtain the following compounds:

    __________________________________________________________________________    1A                       .sup.1 H NMR(CDCl.sub.3 +drop of CD.sub.3 OD,                             200    3 #STR55##                MHz)δ 1.50-2.00(5H, m), 2.25(1H, dd,                             J=13.00 and 5.00Hz), 3.38(3H, s, NCH.sub.3),                             4.15(2H, s, CH.sub.2 C.sub.6 H.sub.4 F),                             4.72(1H, t, J=7.00Hz), 4.85(1H, t, J=7.00Hz),                             6.95 and 7.30(4H, 2d, J=10Hz, C.sub.6 H.sub.4                             F)    1B                       .sup.1 H NMR(CDCl.sub.3 +drop of CD.sub.3 OD,                             300    6 #STR56##                MHz)δ 1.50-2.00(5H, m), 2.28(1H, dd,                             J=13.50 and 5.20Hz), 3.38(3H, s, NCH.sub.3),                             3.50(3H, s, OCH.sub.3), 4.10(2H, s, CH.sub.2                             C.sub.6 H.sub.4 OMe), 4.72(1H, t, J=7.00Hz),                             4.88(1H, t, J=7.00Hz), 6.85 and 7.25(4H, 2d,                             J=10.0Hz, C.sub.6 H.sub.4 OMe)    1C                       .sup.1 H NMR(CDCl.sub.3 +drop of CD.sub.3 OD,                             300    5 #STR57##               MHz)δ 1.50-2.00(5H, m), 2.25(1H, dd,                             J=13.50 and 5.20Hz), 3.35(3H, s, NCH.sub.3),                             4.22(2H, s, CH.sub.2 C.sub.6 H.sub.4 CF.sub.3),                             4.72(1H, t, J=7.00Hz), 4.88(1H, t, J=7.00Hz),                             7.48 and 7.58(4H, 2d, J=8.0Hz, C.sub.6 H.sub.4                             CF.sub.3)    __________________________________________________________________________

EXAMPLE 2 ##STR58##

Dissolve compound 1.4d (2.0 g) in 100 mL of absolute EtOH, add 5 mL ofEtOH saturated with HCl gas and 20% Pd(OH)₂ (2.0 g). Hydrogenate thereaction mixture at 60 psi for 24 h. Basify the reaction with NH₄ OH,filter and evaporate the solvent. Redissolve the residue in CH₂ Cl₂,wash with water, dry and evaporate the solvent. Column chromatograph theresidue (95:5 CH₂ Cl₂ :MeOH) to obtain the title compound: ¹ H NMR(CDCl₃ +drop of CD₃ OD, 300 MHz) δ 1.50-2.00 (5 H, m), 2.25 (1 H, dd,J═13.50 and 5.20 Hz), 2.95 (6 H, t, J═7.00 Hz), 4.88 (1 H, t, J═7.00Hz), 6.70 and 7.15 (4 H, 2 d, J═8.0 Hz, C₆ H₄ NMe₂).

Using the same procedure, treat the compounds 1.4e and 1.4f to obtaincompounds 2A and 2B, respectively:

    __________________________________________________________________________    2A                       .sup.1 H NMR(CDCl.sub.3 +drop of CD.sub.3 OD,                             300    4 #STR59##               MHz)δ 1.50-2.00(5H, m), 2.25(1H, dd,                             J=13.50 and 5.20Hz), 3.40(3H, s, NCH.sub.3),                             3.85(9H, s, 3OCH.sub.3), 4.10(2H, s, CH.sub.2                             C.sub.6 H.sub.4 OMe), 4.72(1H, t, J=7.00Hz),                             4.88(1H, t, J=7.00Hz), 6.50(2H, s, C.sub.6                             H.sub.2 (OMe).sub.3)    2B                       .sup.1 H NMR(CDCl.sub.3 +drop of CD.sub.3 OD,                             200    5 #STR60##               MHz)δ 1.50-2.00(5H, m), 2.25(1H, dd,                             J=13.00 and 5.20Hz), 3.35(3H, s, NCH.sub.3),                             3.85 and 3.88(6H, 2s, 2OCH.sub.3), 4.10(2H, s,                             CH.sub.2 C.sub.6 H.sub.4 (OMe).sub.2), 4.75(1H,                             t, J=7.00 Hz), 4.85(1H, t, J=7.00Hz), 6.85(3H, m                             C.sub.6 H.sub.3 (OMe).sub.2)    __________________________________________________________________________

EXAMPLE 3 ##STR61## Generate LDA (1.2 mmol) in THF (15 mL and cool to-78° C. Add a THF solutionof(+)-cis-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylmethyl)-cyclopent4,5!imidazo 2,1-b!purin-4-one (1.0 mmol) and stir the reaction for 0.5 hat -78° C. Add a solution of 4-benzyloxybenzaldehyde (1.0 mmol) in THF,slowly warm the reaction mixture to -40° C. and stir for 0.5 h at -40°C. Quench the reaction with a saturated NH₄ Cl solution and evaporatethe solvent. Proceed as described in Example 2 to obtain the titlecompound: ¹ H NMR (CDCl₃ +drop of CD₃ OD, 300 MHz) δ 1.60 (1 H, m),1.70-2.00 (4 H, m), 2.20 (1 H, dd, J═10.00 dn 4.00 Hz), 3.30 (3 H, s,NCH₃), 4.20 (2 H, s, CH₂ C₆ H₄ OH), 4.72 (1 H, t, J═7.00 Hz), 6.75 and7.12 (4 H, 2 d, J═8.0 Hz, C₆ H₄ OH).

Using appropriate starting materials and essentially the same procedure,the following compounds can also be prepared:

    __________________________________________________________________________    3A                          .sup.1 H NMR(CDCl.sub.3 +drop of CD.sub.3 OD,                                200    7 #STR62##                  MHz)δ 1.60-2.00(5H, m), 2.28(1H, dd,                                J=10.00 and 5.00Hz), 2.32(3H, s, C.sub.6                                H.sub.4 CH.sub.3), 3.35(3H, s, NCH.sub.3),                                4.12(2H,  s, CH.sub.2 C.sub.6 H.sub.4 Me),                                4.72(1H, t, J=7.00Hz), 4.88(1H, t, J=7.00Hz),                                7.10 and 7.20(4H, 2d, J=8.0Hz, C.sub.6                                H.sub.4 CH.sub.3)    3B                          .sup.1 H NMR(CDCl.sub.3 +drop of CD.sub.3 OD,                                200    8 #STR63##                  MHz)δ 1.50-2.00(5H, m), 2.28(1H, dd,                                J=10.00 and 5.00Hz), 3.35(3H, s, NCH.sub.3),                                4.18(2H, s, CH.sub.2 C.sub.6 H.sub.4 OCF.sub.3                                ), 4.72(1H, t, J=7.00Hz), 4.88(1H, t,                                J=7.00Hz), 7.15 and 7.40(4H, 2d, J=8.0Hz,                                C.sub.6 H.sub.4 OCF.sub.3)    3C                          .sup.1 H-NMR(300 MHz, CDCl.sub.3)δ                                1.47-2.31    9 #STR64##                  (m, 6H), 3.05-3.15(m, 4H), 3.38(s, 3H),                                3.78-3.86(m, 4H), 4.08(s, 2H), 4.73(t, 1H,                                J=7Hz), 4.88(t, 1H, J=7Hz), 6.84(d, 2H,                                J=6.7Hz), 7.24(d, 2H, J=6.8Hz);                                 α!.sub.D.sup.25 = +79° (c 0.7,                                EtOH);    3D                          .sup.1 H-NMR(200 MHz, CDCl.sub.3)δ                                1.57-2.35    0 #STR65##                  (m, 10H), 3.21-3.29(m, 4H), 3.40(s, 3H),                                4.05(s, 2H), 4.75(t, 1H, J=6.9Hz), 4.91(t,                                1H, J=7.0Hz), 6.50(d, 2H, J=8.4Hz), 7.14 (d,                                2H, J=8.4Hz); Cl MS 391(M+1, 100%)    3E                           α!.sub.D.sup.22.5 = +134.3°                                (EtOH)    1 #STR66##    3F                          mp=259-260° C.;    2 #STR67##                  FAB MS 390(m+H, 100%)    3G                           α!.sub.D.sup.22.5 = +108.4°                                (EtOH)    3 #STR68##    3H                          FAB MS 398(m+H, 100%)    4 #STR69##    __________________________________________________________________________

EXAMPLE 4 ##STR70## Step 1: React(+)-cis-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylmethyl)-cyclopent4,5!imidazo 2,1-b!purin-4-one with LDA, then with4-(1H-pyrrol-1-yl)benzaldehyde in a manner similar to that described inExample 3.

Step 2: Add sodium pellets (24 mg, 1.0 mmol) to a solution of theproduct of Step 1 (54 mg, 0.11 mmol) in anhydrous THF (15 mL) and liquidammonia (35 mL) at -78° C. Stir the mixture for 5 min at -78° C., thenadd solid NH₄ Cl to quench the reacton. Allow the liquid ammonia toevaporate at room temperature. Triturate the residue with CH₂ Cl₂ /CH₃OH (9:1), filter, dry over MgSO₄ and concentrate. Chromatograph theresidue, eluting with CHCl₃ /MeOH (95:5) to obtain 9.8 mg (23%) of thetitle compound. Cl MS 387 (M+1, 100%); ¹ H-NMR (300 MHz, CDCl₃) d1.50-2.67 (m, 6H), 3.36 (s, 3H), 4.15 (s, 2H), 4.70 (t, 1H, J=6 Hz),4.87 (t, 1H, J=8 Hz), 6.28-6.30 (m, 2H), 7.00-7.02 (m, 2H), 7.23-7.38(m, 4H)

EXAMPLE 5 ##STR71## Step 1: Heat a mixture of the compound of Example1.4b (4.40 g) and pyridine hydrochloride (5.8 g) to 170° C. for 4.5 h.Cool to room temperature, add an ice cold solution of saturated NaHCO₃,extract with CH₂ Cl₂, wash the organic layers with brine, dry overMgSO₄, filter and concentrate to yield a solid, FAB MS 428 (M+H).

Step 2: Suspend a portion of the product of Step 1 (0.62 9) in DMF (80mL), cool to 0° C., add N-phenyl trifluoromethane sulfonimde (0.57 g)and K₂ CO₃ (0.39 g). Allow the reaction to warm to room temperatureovernight, then pour the reaction mixture into ice water (0.7 L),extract with EtOAc, wash the organic layer with brine, dry over MgSO₄,filter and concentrate to dryness.

Step 3: Dissolve a portion of the residue of Step 2 (0.52 g) in dioxane(13 mL), add 4-methoxyphenyltrimethyltin (0.5 g) (prepared from reactionof 4-bromoanisole with t-butyl lithium and trimethyltin chloride), LiCl(0.125 g), Pd(PPh₃)₄ (0.04 g), and a catalytic amount of BHT. Heat thereaction mixture to reflux for 15 h under a nitrogen atmosphere, cool toroom temperature, basify with 10% NH₄ OH, and extract with EtOAc. Washthe organic layer with brine, dry over MgSO₄, filter and concentrate todryness. Chromatograph the residue on silica gel using CH₂ Cl₂ /CH₃ OH(90:10) to give a light yellow solid, El MS (70 ev) 517 (m+, 100%).

Step 4: Dissolve the solid from Step 3 (0.36 g) in CH₃ OH (50 mL), addNH₄ HCO₂ (0.66 g) and 10% Pd/C (0.3 g ). Heat this mixture to reflux for43 h, then add more NH₄ HCO₂ (0.66 g) and continue heating for 8 h, coolto room temperature, filter through celite, concentrate to dryness andpartition the residue between 10% NaHCO₃ and CH₂ Cl₂. Dry the organiclayers over MgSO₄, concentrate to dryness and chromatograph the residueon silica gel using CH₂ Cl₂ /EtOH/NH₄ OH (90:10:1) to give the titlecompound as a colorless solid: α!_(D) ²¹ =+113.9° (MeOH); EV MS (70 ev)427 (m+, 60%), 398 (100%).

EXAMPLE 6 ##STR72## Step 1: To a solution ofcis-5,6a,7,8,9,9a-hexahydro-5-methylcyclopenta- 4,5!-imidazo2,1-b!purin-4(3H)-one (3.38 g, 14.6 mmol) and NaOAc (1.44 g, 17.5 mmol)in HOAc (70 mL) at room temperature and under N₂, add bromine (0.91 mL,17.5 mmol). Stir at 50° C. for 16 h, filter the solids, wash with CHCl₃and air dry to obtain the 2-bromo derivative as a white solid (3.75 g,83%). ¹ H-NMR (400 MHz, DMSO-d₆) δ 1.68-2.24 (m, 6H), 3.32 (s, 3H), 4.81(t, 1H, J=7 Hz), 5.19 (t, 1H, J=7 Hz), 10.18 (br s,1H); Cl MS 232(100%), 310 (27%), 312 (25%); α!_(D) ¹⁹.8 =+100.6° (c 0.63, CH₃ OH)

Step 2: To a solution of zinc dust (1.70 g, 26 mmol) in dry THF at roomtemperature, under N₂, add 1,2-dibromoethane (0.086 mL, 1.0 mmol) andstir at 65° C. for 1 min. At 0° C., add, dropwise, a solution of2-bromomethylnaphthalene (4.75 g, 21.5 mmol) in dry THF (11 mL) and stirat 0° C. for 1 h, then at room temperature for 1 h. Heat a portion ofthe supernatant (3.3 mL, approx. 5.4 mmol) with the product of Step 1(0.166 g, 0.535 mmol), Pd(PPh₃)₄ (0.062 g, 0.0544 mmol) and PPh₃ (0.028g, 0.11 mmol) in NMP (2 mL) at 100° C. under argon for 20 h. Evaporatethe solvent, dissolve the resultant residue in CHCl₃ --CH₃ OH (9-1),wash with sat'd NaHCO₃, dry over MgSO₄ and concentrate. Separate byflash chromatography, eluting with CHCl₃ --CH₃ OH (97-3) to obtain thetitle compound (0.079 g, 40%). ¹ H-NMR (400 MHz, CDCl₃) δ 1.47-2.28 (m,6H), 3.30 (s, 3H), 4.27-4.35 (AB q, 2H), 4.68 (t, 1H, J=7 Hz), 4.81 (t,1H, J=7 Hz), 7.40-7.80 (m, 7H); Cl MS 372 (M+1, 100%); α!_(D) ²¹.7=+78.5° (c 0.41, CHCl₃).

EXAMPLE 7 ##STR73##

In a manner similar to that of Example 6, using appropriate startingmaterials, prepare the title compound: ¹ H-NMR (400 MHz, CDCl₃) δ1.49-2.28 (m, 6H), 3.36 (s, 3H), 4.13 (s, 2H), 4.73 (t, 1H, J=7 Hz),4.87 (t, 1H, J=7 Hz), 7.26-7.27 (m, 4H); Cl MS 356 (100%), 358 (33%);α!_(D) ²¹.8 =+101.0° (c 0.41, CHCl₃).

EXAMPLE 8 ##STR74## Step 1: Reflux a solution of ethyl2-benzyl-4-amino-5-imidazole carboxylate (0.89 g, 3.63 mmol) and CH₃ NCO(8 mL) in pyridine (15 mL) for 2 h. Cool the reaction mixture, evaporatethe solvent, extract the residue with EtOAc, wash with water, dry andevaporate. Column chromatograph the residue, eluting with 2% MeOH in CH₂Cl₂. TLC R_(f) =0.3 (5% MeOH in CH₂ Cl₂); MS 303 (M+1); ¹ H NMR (CDCl₃,200 MHz) δ 1.32 (3H, t, CH₃ CH₂ O), 2.90 (3H, d, NHCH₃), 4.05 (2H, s,CH₂ Ph), 4.30 (2H, q, OCH₂ Me), 7.35 (5H, m, C₆ H₅).

Step 2: Reflux the solution of the product of Step 1 (0.85 g) in 10% (byweight) NaOH (15 mL) for 0.5 h. Cool the reaction mixture, adjust thereaction mixture to pH6 with HOAc and filter. Dry the solid at highvacuum overnight. ¹ H NM (DMSO, 200 MHz) δ 3.15 (3H, s, NCH₃), 3.95 (2H,s, CH₂ Ph), 7.28 (5H, m, C₆ H₅).

Step 3: Reflux a solution of the product of Step 2 (0.84 g) in POCl₃ (30mL) for 24 h. Cool the reaction mixture, pour into hexane (100 mL) andlet stand at room temperature for 0.5 h. Decant the solvent, treat theresulting gum with ice cold water, neutralize it with 2N NaOH, extractwith CH₂ Cl₂ (2×100 mL), dry and evaporate the solvent. Columnchromatograph the residue, eluting with 5% MeOH in CH₂ Cl₂. TLC R_(f)=0.45 (5% MeOH in CH₂ Cl₂); ¹ H NMR (CDCl₃, 200 MHz) δ 3.80 (3H, s,NCH₃), 4.30 (2H, s, CH₂ Ph), 7.35 (5H, m, C₆ H₅).

Step 4: Suspend the product of Step 3 (0.2 g, 0.73 mmol),1-amino-1-cyclopentane methanol (0.17 g, 1.45 mmol) and (i-Pr₂ NEt)(0.25 mL, 1.45 mmol) in NMP (2 mL) and keep the reaction mixture at 130°C. for 6 h. Pour the reaction mixture on ice/water to precipitate theproduct. Filter the product and dry it under high vacuum. TLC R_(f)=0.28 (5% CH₃ OH in CH₂ Cl₂); MS 354 (M+1) Fab; ¹ H NMR (CDCl₃ + drop ofCD₃ OD, 200 MHz) δ 1.60-2.00 (8H, m), 3.45 (3H, s, NCH₃), 3.80 (2H, s,CH₂ OH), 4.26 (2H, s, CH₂ Ph), 7.32 (5H, m, C₆ H₅).

Step 5: Treat a suspension of the product of Step 4 (0.08 g, 0.22 mmol)in CH₂ Cl₂ (10 mL) with SOCl₂ (0.05 mL) at room temperature overnight.Dilute the reaction mixture with CH₂ Cl₂, wash with cold 1N NaOH, dryand evaporate. Column chromatograph the crude title compound, elutingwith 5% MeOH in CH₂ Cl₂ to obtain the title compound. MS 336 (M+1); ¹ HNMR (CDCl₃ + drop of CD₃ OD, 200 MHz) δ 1.60-2.00 (8H, m), 3.56 (3H, s,NCH₃), 4.18 (2H, bs, CH₂), 4.22 (2H, s, CH₂ Ph), 7.30 (5H, m, C₆ H₅).

EXAMPLE 9 ##STR75## Step 1: Treat a solution of the product of Step 3 ofEx. 8 (0.16 g, 0.58 mmol) and 2-amino-2-methyl propanol (0.13 g, 1.45mmol) according to procedure described in Step 4 of Ex. 8: MS 328 (M+1)FAB; ¹ H NMR (CDCl₃ + drop of CD₃ OD, 200 MHz) δ 1.45 (6H, s, (CH₃)₂ C),3.45 (3H, s, NCH₃), 3.75 (2H, s, CH₂ OH), 4.20 (2H, s, CH₂ Ph), 7.30(5H, m, C₆ H₅).

Step 2: Treat the product of Step 1 according to the procedure of Step 5in Ex. 8 to produce the crude title compound. Column chromatograph thecrude product, eluting with 7% CH₃ OH in CH₂ Cl₂ to obtain the titlecompound. TLC R_(f) =0.60 (7% CH₃ OH-- in CH₂ Cl₂); MS 310 (M+1); ¹ HNMR (CDCl₃ + drop of CD₃ OD, 200 MHz) δ 1.45 (6H, S, (CH₃)₂ C), 3.40(3H, s, NCH₃), 3.90 (2H, s, CH₂), 4.16 (2H, s, CH₂ Ph), 7.35 (5H, m, C₆H₅).

EXAMPLE 10 ##STR76## Step 1: Treat the product of Ex. 8, Step 3 (0.20 g,0.73 mmol) and (R)-2-amino-3-methyl-1-butanol (0.15 g, 1.45 mmol) usingthe procedure of Ex. 8, Step 4: MS 341; TLC R_(f) =0.40 (10% MeOH in CH₂Cl₂); ¹ H NMR (CDCl₃ + drop of CD₃ OD, 200 MHz) δ 0.96 and 0.98 (6H, 2d,(CH₃)₂ CH), 2.00 (1H, dt, CH(Me)₂), 3.45 (3H, s, NCH₃), 3.65 and 3.75(2H, 2dd, J=15.00 and 6.5 Hz, CH₂ OH), 4.12 (2H, s, CH₂ Ph), 7.28 (5H,m, C₆ H₅).

Step 2: Treat the product of Step 1 (0.11 g, 0.32 mmol) with SOCl₂ (0.14g, 0.08 mL) as described in Step 5 of Ex. 8. Column chromatograph thecrude product, eluting with 7% CH₃ OH--CH₂ Cl₂ to obtain the titlecompound. TLC R_(f) =0.45 (10% CH₃ OH in CH₂ Cl₂); MS 324 (M+1); ¹ H NMR(CDCl₃ + drop of CD₃ OD, 200 MHz) δ 1.00 and 1.05 (6H, 2d, (CH₃)₂ CH),2.10 (1H, m), 3.62 (3H, s, NCH₃), 4.25 (2H, s, CH₂ Ph), 4.15 (1H, m),4.40 (2H, m), 7.28 (5H, m, C₆ H₅).

EXAMPLE 11 ##STR77## Step 1: ##STR78## Heat a mixture of2-choloro-1-methyl-7-(phenylmethyl)purin-6-one (1 g),1-amino-7-hydroxybicyclo 3.3.0!octane hydrochloride (0.65 g), (i-pr₂NEt) (1.25) and NMP (3) in a sealed tube at 14° C. or 60 h. Cool thereaction to room temperature and pour into water. Collect the solid byfiltration, dissolve it in CH₂ Cl₂ and chromatograph on silica gel,eluting with CH₂ Cl₂ /CH₃ OH (95/5) to give a solid. FAB MS 380 (m+H,100%). Dissolve a portion of this solid (0.82 g) in CH₂ Cl₂ (5 mL), andadd SOCl₂ (0.5 mL). Stir the reaction mixture for 2 h,partition betweenNaHCO₃ and CH₂ Cl₂. Wash the organic layer with brine, dry over MgSO₄,filter and concentrate to dryness to obtain a solid. EI MS (70 ev) 361(M+, 100%).

Step 2: ##STR79## Add the product of Step 1 (0.36 g) to a solution ofLDA (1.2 mmol) in THF (2 mL) at -78° C. Stir the reaction mixture for0.5 h, then add a solution of piperonal (0.18 g) in THF and continuestirring at -78° C. for 1 h. Quench the reaction with HOAc (0.1 mL) andallow the reaction mixture to warm to room temperature, then partitionbetween EtOAc and NaHCO₃. Wash the organic layer with brine, dry overMgSO₄, filter and concentrate to dryness to give a solid. El MS (70 ev)511 (M+, 100%).

Step 3: Place a mixture of the product of Step 2 (0.37 g), 20% palladiumhydroxide on charcoal (0.15 g), EtOH (75 mL) and conc. HCl (0.6 mL)under a H₂ atmosphere (60 psi) for 60 h. Remove the catalyst byfiltration through celite, concentrate the filtrate to dryness andpartition the residue between NaHCO₃ and CH₂ Cl₂. Wash the organic layerwith brine, dry over MgSO4, filter and concentrate to dryness.Chromatograph this residue on silica gel, eluting with CH₂ Cl₂ /CH₃ OH(95/5) to obtain the title compound as a colorless solid, mp 239-240°C., El HRMS calc for C₂₂ H₂₃ N₅ O₃ 405.1801, found 405.1806.

EXAMPLE 12 ##STR80## Step 1:

A: Add m-CPBA (9.5 g, 0.55 mol) to a solution of 1,4-dihydrofuran (3.8mL, 0.050 mol) in CH₂ Cl₂ (100 mL) at room temperature and stir for 16h. Filter the solids, wash the filtrate with NaHCO₃ (sat.), dry overMgSO₄, and concentrate to give a clear oil (2.2 g, 51%). ¹ H-NMR (300MHz, CDCl₃) δ 3.65 (d, 2H, J=10.5 Hz), 3.79 (s, 2H), 4.02 (d, 2H, J=10.6Hz).

B: Heat R-(+)-α-methylbenzylamine (14 mL, 0.011 mol) with the product ofStep A (10 g) and water (2 mL) at 100° C. for 24 h. Cool the reactionmixture and recrystallize the solid twice from CH₂ Cl2-hexanes (1.2 g).HPLC showed>91% purity. ¹ H-NMR (300 MHz, CDCl₃) 81.37 (d, 3H, J=6.7Hz), 1.90 (br s, 2H), 3.03-3.07 (m, 1H), 3.36 (dd, 1H, J=9.3, 4.1 Hz),3.66 (dd, 1H, J=9.8, 2.4 Hz), 3.86-3.92 (m, 2H), 3.98 (dd, 1H, J=9.8,4.7 Hz), 4.22-4.25 (m, 1H), 7.26-7.37 (m, 5H).

C: Heat the product of Step B (750 mg) with NH₄ HCO₂ (820 mg) inrefluxing CH₃ OH (30 mL) over Pd/C (700 mg) for 1 h. Cool, filter, andconcentrate the mixture (300 mg, 95%). α!²⁵ D=-11° (c 0.2, MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 2.40 (br s, 3H), 3.74-3.96 (m, 3H), 4.26-4.34(m, 2H), 4.44-4.48 (m, 1H).

Step 2:

A: Stir 6-amino-3-methyl-5-(phenylmethyleneamino)pyrimidine-2,4-dione(2.46 g), 4-trifluoromethylphenylacetic acid (5.1 g) and DEC (4.8 g) indry DMF at room temperature for 4 h. Pour the reaction mixture over ice,filter the solids and wash with Et₂ O (3.80 g, 88%). ¹ H NMR (DMSO-d₆,300 MHz) δ 3.00 (s, 3H), 3.58 (s, 2H), 4.51 (d, 1H, J=14 Hz), 4.59 (d,1H, J=14 Hz), 6.27 (br s, 2H), 7.22-7.32 (m, 5H), 7.38 (d, 2H, J=8 Hz),4.59 (d, 2H, J=8 Hz), 10.45 (br s, 1H).

B: Reflux the product of Step 2A (1.8 g) in POCl₃ (30 mL) for 16 h. Coolthe reaction mixture and dilute with hexanes (600 mL). After 4 h, decantthe liquid layer from the oily residue, dissolve the residue in CH₂ Cl₂--CH₃ OH (9-1), wash with NaHCO₃ (sat.), dry (MgSO₄), and concentrate.Purify the residue by flash chromatography, eluting with CHCl₃ --CH₃ OH(97-3) (700 mg, 36%). ¹ H NMR (CDCl₃, 300 MHz) δ 3.72 (s, 3H), 4.15 (s,2H), 5.54 (s, 2H), 6.99 (d, 2H, J=7.9 Hz), 7.19-7.34 (m, 5H), 7.49 (d,2H, J=7.9 Hz).

Step 3: Heat the product of Step 2B (0.68 g, 1.57 mmol), the product ofStep 1C (0.28 g), and Et₃ N (0.9 mL) in 20 mL of NMP at 120° C. for 16h. Concentrate the mixture to remove NMP. Dissolve the residue in CH₂Cl₂, wash with NaHCO₃ (sat.), dry over MgSO₄, and concentrate. Purifythe residue by flash chromatography, eluting with CHCl₃ --CH₃ OH (95-5)(320 mg, 54%). To a solution of the resultant compound (320 mg) and Et₃N (0.6 mL) in CH₂ Cl₂ (25 mL), add, dropwise, CH₃ SO₂ Cl (0.12 mL) andstir for 16 h. Wash the solution with NaHCO₃ (sat.), dry (MgSO₄), andconcentrate. Purify the resultant residue by flash chromatography,eluting with CHCl₃ --CH₃ OH (97-3) (250 mg, 78%). ¹ H NMR (CDCl₃, 300MHz) δ 3.50 (s, 3H), 3.72-3.78 (m, 2H), 4.10 (s, 2H), 4.29 (d, 1H, J=9.2Hz), 4.47 (d, 1H, J=11 Hz), 4.96-5.00 (m, 1H), 5.12-5.17 (m, 1H), 5.40(d, 1H, J=16 Hz), 5.48 (d, 1H, J=16 Hz), 7.02-7.05 (m, 2H), 7.15 (d, 2H,J=8.3 Hz), 7.26-7.30 (m, 3H), 7.51 (d, 2H, J=8.4 Hz).

Step 4: Reflux the product of Step 3 (190 mg), NH₄ HCO₂ (200 mg), and10% Pd/C (150 mg) in CH₃ OH (25 mL) for 1.5 h. Filter the mixture andwash the solids with CH₂ Cl₂ --CH₃ OH (9-1). Combine the filtrate andthe washings, wash with NaHCO₃ (sat.), dry (MgSO₄), and concentrate.Purify the resultant residue by flash chromatography, eluting with CHCl₃--CH₃ OH (95-5) to obtain the title compound (100 mg) as a white solid.α!²⁵ D=+125° (c 0.4, EtOH); ¹ H NMR (CDCl₃, 300 MHz) δ 3.48 (s, 3H),3.69-3.76 (m, 2H), 4.19 (d, 1H, J=10.5 Hz), 4.24 (s, 2H), 4.42 (d, 1H,J=11.3 Hz), 4.92-4.96 (m, 1H), 5.10-5.14 (m, 1H), 7.46 (d, 2H, J=8.0Hz), 7.58 (d, 2H, J=8.0 Hz).

EXAMPLE 13 ##STR81## To a suspension of 1.5 g of the product ofPreparation 5 in 45 ml CH₂ Cl₂ at room temperature under N₂, add 1.7 mlof SOCl₂. Stir the suspension until the reaction is complete, about 18hours. Remove the volatiles under vacuum, dissolve the residue in CH₃ OHand treat with excess Na₂ CO₃ plus NaHCO₃. Stir for 30 minutes andfilter. Remove CH₃ OH from the filtrate, dissolve the residue in CH₃ CN,filter and remove CH₃ CN under reduced pressure. Dissolve the foam thusobtained in water, stir with an anion exchange resin such as IRA 401 SOH resin® (trademark of the Rohm and Haas Chemical Company,Philadelphia, Pa.) for 20 minutes. Filter and concentrate the aqueoussolution, dissolve the residue thus obtained in CH₂ Cl₂ and pass througha silica plug with 5% CH₃ OH in CH₂ Cl₂ as eluant. Concentrate theeluant and crystallize the resultant foam from CH₃ CN to obtain 0.9 g ofthe title compound, a solid.

α!_(D) ²⁶ =+155°; MS (FAB) 246 (M+H).

EXAMPLE 14 ##STR82##

To a stirred solution of 86.5 g of the crude product of Preparation 5.1in 1.3 L CH₃ CN under N₂, kept at ˜20° C. (water bath), add slowly 39 mLSOCl₂. Remove the water bath and stir vigorously at room temperatureuntil complete reaction (about 12 to 18 hr) as judged by tlc.Concentrate under reduced pressure, take the resultant gum in a mixtureof 1 L CH₂ Cl₂ and 700 mL H₂ O, stir this mixture and neutralize to a pHof 9.5 with slow addition of NH₄ OH. Filter this mixture to removesolids and wash the solids with CH₂ Cl₂. Combine the filtrate and thewashes, separate the layers, treat the aqueous layer with ˜1 g NaCl andthen reextract with 2×500 mL CH₂ Cl₂. Dry the combined organic layer(anhyd. MgSO₄) and concentrate in vacuo to obtain 74 g of a light brownsolid. Slurry this solid in 225 mL EtOAc to obtain 35.6 g of off-whitetitle compound. Concentrate the EtOAc filtrate and washes to obtain ˜37g of a brown-black solid. Subject this solid to silica gel columnchromatography to obtain an additional 3.6 g of product.

Chromatograph the above product on silica gel to obtain a light tansolid as an analytical sample of the title compound. M.p. 235-237° C.;MS (El): 389 (M+); Cl(NH₄): 390 (M+H); α!_(D) ²⁵ =+104° (c 1.0, MeOH).

Pharmaceutical Preparations

The compounds of formula I can be combined with a suitablepharmaceutical carrier to prepare a pharmaceutical composition suitablefor parenteral or oral administration. Such pharmaceutical compositionsare useful in the treatment of cardiovascular and pulmonary disorderssuch as mammalian hypertension and bronchoconstriction.

The effective daily antihypertensive dose (ED₅₀) of the presentcompounds will typically be in the range of about 1 to about 100 mg/kgof mammalian body weight, administered in single or divided doses. Theexact dosage to be administered can be determined by the attendingclinician and is dependent upon where the particular compound lieswithin the above cited range, as well as upon the age, weight andcondition of the individual.

Generally, in treating humans in need of treatment for hypertension orbronchoconstriction, the present compounds can be administered in adosage range of about 10 to about 500 mg per patient generally given anumber of times per day, providing a total daily dosage of from about 10to about 2000 mg per day.

The compositions of the present invention can be administered orally orparenterally. Typical injectable formulations include solutions andsuspensions. Typical oral formulations include tablets, capsules,syrups, suspensions and elixirs. Also contemplated are mechanicaldelivery systems, e.g. transdermal dosage forms.

The typical acceptable pharmaceutical carriers for use in theformulations described above are exemplified by sugars such as lactose,sucrose, mannitol and sorbitol; starches such as cornstarch, tapiocastarch and potato starch; cellulose and derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and methyl cellulose; calciumphosphates such as dicalcium phosphate and tricalcium phosphate; sodiumsulfate; calcium sulfate; polyvinylpyrrolidone, polyvinyl alcohol;stearic acid; alkaline earth metal stearates such as magnesium stearateand calcium stearate, stearic acid, vegetable oils such as peanut oil,cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationicand anionic surfactants; ethylene glycol polymers; beta-cyclodextrin;fatty alcohols and hydrolyzed cereal solids; as well as other non-toxiccompatible fillers, binders, disintegrants, buffers, preservatives,antioxidants, lubricants, flavoring agents, and the like commonly usedin pharmaceutical formulations.

Following are typical examples of oral and parenteral formulations,wherein the term "Active Ingredient" refers to a compound of formula I.

    ______________________________________    Capsule            Amount (mg)    ______________________________________    Active Ingredient  250.0  125.0    Lactose            173.0  86.5    Corn Starch        75.0   37.5    Magnesium Stearate 2.0    1.0    TOTAL              500.0  250.0    ______________________________________

Blend the active ingredient, lactose and corn starch until uniform; thenblend the magnesium stearate into the resulting powder.

Encapsulate the mixture into suitably sized two-piece hard gelatincapsules.

    ______________________________________    Tablet            Amount (mg)    ______________________________________    Active Ingredient 250.0     125.0    Lactose           161.0     80.5    Corn Starch       12.0      6.0    Water (per thousand tablets)                      120 ml    60 ml                      (evaporates)                                (evaporates)    Corn Starch       75.0      37.5    Magnesium Stearate                      2.0       1.0    TOTAL             500.0     250.0    ______________________________________

Blend the active ingredient with the lactose until uniform. Blend thesmaller quantity of corn starch with the water and add the resultingcorn starch paste then mix until a uniform wet mass is formed. Add theremaining corn starch to the remaining wet mass and mix until uniformgranules are obtained. Screen the granules through a suitable millingmachine, using a 3/4 inch stainless steel screen. Dry the milledgranules in a suitable drying oven until the desired moisture content isobtained. Mill the dried granules through a suitable milling machineusing a 16 mesh stainless steel screen. Blend in the magnesium stearateand compress the resulting mixture into tablets of desired shape,thickness, hardness and disintegration.

    ______________________________________    Injectable Solution                       mg/ml    ______________________________________    Active Ingredient  5.00    Methyl p-hydroxybenzoate                       0.80    Propyl p-hydroxybenzoate                       0.10    Disodium Edetate   0.10    Citric Acid Monohydrate                       0.08    Dextrose           40.0    Water for injection qs. ad.                       1.0 ml    ______________________________________

Dissolve the p-hydroxybenzoates in a portion of water for injection at atemperature of between 60° C. -70° C. and cool the solution to 20° C.-30° C., Charge and dissolve all other excipients and the activeingredient. Bring the solution to final volume, filter it through asterilizing membrane and fill into sterile containers.

Biological Activity of 2-Benzyl Polycyclic Guanines

The present compounds are useful in inhibiting the phosphodiesteraseenzymes. These phosphodiesterase enzymes are known to hydrolyze cGMP insmooth muscle. High levels of cGMP are associated with the relaxation ofvascular smooth muscle, with a consequent subsequent reduction in bloodpressure. Thus, it is believed that by inhibiting thesephosphodiesterase enzymes, cGMP levels in muscle will be eithermaintained or increased, with a subsequent reduction in blood pressure.In vivo antihypertensive activity is determined orally in spontaneouslyhypertensive rats (SHR).

Phosphodiesterase inhibition in vitro:

Compounds are evaluated for inhibition of two phosphodiesterase enzymeswhich hydrolyze cyclic guanosine monophosphate (cGMP). The first enzyme,calcium-calmodulin dependent phosphodiesterase (CaM-PDE), is a partiallypure enzyme aobtained from bovine aorta homogenates and purified byDEAE-cellulose and calmodulin-affinity chromatography. The enzyme isactivated several fold by Ca-calmodulin and is selective for cGMP,although it will also hydrolyze cAMP. The second enzyme, cGMPphosphodiesterase (cGMP-PDE), is a homogeneous enzyme obtained frombovine lung and purified by ion-exchange chromatography, gel filtration,and sucrose gradient centrifugation. cGMP-PDE is highly selective forcGMP. Bovine aorta homogenates and primary cultures of bovine aorticendothelial and vascular smooth muscle cells contain an enzyme withproperties very similar to the lung isozyme.

The enzyme assay is performed using a Biomek Automated PipettingStation. Compounds are dissolved in distilled water or DMSO and dilutedwith 10% DMSO. Compounds are tested at several concentrations at logintervals, typically 0.1, 1.0, 10, and 100 μM final concentration.

Assays contain the following components:

1 μM substrate ³ H-cGMP

50 mM Tris-HCl, pH 7.5, 5 mM MgCl₂

0.5 mg/ml snake venom alkaline phosphatase

0.1 μM Calmodulin and 1 mM CaCl₂ (for CaM-PDE only)

Assays are initiated by addition of enzyme and stopped by addition of 10mM isobutylmethylxanthine, a general phosphodiesterase inhibitor. Assaysare performed for 25 minutes at room temperature to achieve 5-10%hydrolysis of substrate. The negatively charged substrates are thenseparated from guanosine by binding to an anion-exchange resin (AG1-X8)and centrifugation or filtration, and the product is quantitated byscintillation counting in counts per minute (cpm) of the remainingsoluble material. Percent inhibition is calculated as follows:

% Inhibition=100- (cpm compound-blank)/(cpm control-blank)X100!

Activity is expresssed as the IC₅₀ value, ie. the concentration requiredto inhibit activity of enzyme by 50 per cent.

Antihypertensive activity in rats

The ability of the compounds of the present invention to lower bloodpressure can be assessed in vivo in conscious spontaneously hypertensiverats (SHR). SHR males are purchased from Taconic Farms, Germantown, N.Y.and are approximately 16-18 weeks old when anesthetized with ether. Thecaudal (ventral tail) artery is cannulated with polyethylene tubing(PE50) and blood pressure and heart rate are recorded as described byBaum, T. et. al, J. Cardiovasc. Pharmacol. Vol 5, pp. 655-667, (1983).Rats are placed into plastic cylindrical cages where they rapidlyrecover consciousness. Blood pressure and heart rate are allowed tostabilize for approximately 90 minutes prior to compound administration.Compounds are administered orally as solutions or suspensions in 0.4%aqueous methylcellulose vehicle via a feeding needle. The compound or0.4% aqueous methylcellulose vehicle are given in a volume of 4 ml/kg toSHRs that had been fasted overnight. Activity is expressed as the fallin mean blood pressure (MBP) in millimeters of mercury (mm Hg).Compound-induced changes are compared with the changes in an appropriateplacebo group. "NT" means that the compound was not tested in thatassay.

    ______________________________________    ACTIVITY OF 2-BENZYL-TETRACYLCLIC GUANINES             PDE IC.sub.50 SHR Antihypertensive    Example  CaM           Dose    Fall in MBP    Number   (μM)       (mpk)   (mmHg)    ______________________________________     1       0.1           10      47    1A       <0.1          10      49    1B       0.2           10      61    1C       0.6           10      40    2        <0.1          10      40    2A       0.7           3       19    2B       0.4           3       30    3        <0.1          10      21    3A       0.1           10      42    3B       0.6           3       28    3C       0.2           3       23    3D       NT            3       28    3E       0.9           10      29    3F       0.8           10      34    3G       0.3           3       28    3H       <0.1          3       27     4       NT            3       32     5       NT            3       33     6       0.48          3       19     7       0.65          3       27     8       0.1           10      40     9       0.3           10      47    10       0.1           10      39    11       0.2           10      59    12       3.0           3       20    ______________________________________

The activities ofcis-5,6a,7,8,9,9a-hexahydro-5-methyl-2-phenylmethyl)cyclopent4,5!imidazo2,1b!purin-4(3H)-one (Compound A) andcis-5,6a,7,8,9,9a-hexahydro-5-methylcyclopenta- 4,5!imidazo2,1-b!-purin-4(3H)-one (Compound B), compounds specifically disclosed inWO91/19717, are as follows:

    ______________________________________    Cpd.    PDE IC.sub.50 :                         SHR:    ______________________________________    A       CaM: 0.2 μM                         fall in MBP at 25 mpk: 6 mmHg    B       CaM: 33 μM                         fall in MBP at 25 mpk: 32 mmHg                         fall in MBP at 10 mpk: 8 mmHg    ______________________________________

We claim:
 1. A compound having the structural formula ##STR83## or apharmaceutically acceptable salt thereof, wherein: R₁, R₂ and R₃ areindependently selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, halogeno, hydroxy, (di-lower alkyl)amino,4-morpholinyl, 1-pyrrolidinyl, 1-pyrrolyl, --CF₃, --OCF₃, phenyl andmethoxyphenyl; or R₁ and R₂ together are methylenedioxy; or R₁ and R₂together with the carbon atoms to which they are attached form a benzenering; andR^(a) is hydrogen and R^(b) and R^(c), together with the carbonatoms to which they are attached, form a saturated ring of 5 carbons; orR^(a) is lower alkyl, R^(b) is hydrogen or lower alkyl, and R^(c) ishydrogen; or R^(a), R^(b) and the carbon atom to which they are attachedform a saturated ring of 5-7 carbons, and R^(c) is hydrogen; or R^(a) ishydrogen, and R^(b), R^(c) and the carbon atoms to which they areattached form a tetrahydrofuran ring; or R^(a) and R^(b), together withthe carbon atom to which they are attached, and R^(b) and R^(c),together with the carbon atoms to which they are attached, each form asaturated ring of 5-7 carbons.
 2. A compound of claim 1 wherein R₁ andR₃ are each hydrogen.
 3. A compound of claim 1 wherein R₁ and R₃ areeach hydrogen and R₂ is hydrogen, --CF₃, --OCF₃, methyl, methoxy,fluoro, phenyl, methoxyphenyl, dimethylamino, 1-pyrrolidinyl or1-pyrrolyl; or wherein R₁ and R₂ together form a methylenedioxy groupand R₃ is hydrogen.
 4. A compound of claim 1 wherein R^(a) is hydrogenand R^(b) and R^(c), together with the carbon atoms to which they areattached, form a saturated ring of 5 carbons; or R^(a) is lower alkyl,R^(b) is hydrogen or lower alkyl, and R^(c) is hydrogen; or R^(a), R^(b)and the carbon atom to which they are attached form a saturated ring of5 carbons, and R^(c) is hydrogen; or R^(a) is hydrogen, and R^(b), R^(c)and the carbon atoms to which they are attached form a tetrahydrofuranring; or R^(a) and R^(b), together with the carbon atom to which theyare attached, and R^(b) and R^(c), together with the carbon atoms towhich they are attached, each form a saturated ring of 5 carbons.
 5. Acompound of claim 1 wherein R^(a) is lower alkyl, R^(b) is lower alkylor hydrogen, and R^(c) is hydrogen; R^(a) and R^(b) and the carbon atomto which they are attached form a saturated ring of 5 carbons and R^(c)is hydrogen; or R^(a) is hydrogen and R^(b) and R^(c), together with thecarbon atoms to which they are attached, form a saturated ring of 5carbons.
 6. A compound of claim 1 having the structural formula##STR84## wherein R^(a) is hydrogen and R^(b) and R^(c), together withthe carbon atoms to which they are attached, form a saturated ring of 5carbons, and wherein R₁, R₂ and R₃ are as defined in the followingtable:

    ______________________________________    R.sub.1   R.sub.2           R.sub.3    ______________________________________    H         H                 H    --OCH.sub.3              H                 H    H         F                 H    H         --OCH.sub.3       H    H         OH                H    H         --CH.sub.3        H    H         (CH.sub.3).sub.2 N--                                H    --OCH.sub.3              --OCH.sub.3       --OCH.sub.3    --OCH.sub.3              --OCH.sub.3       H    --CF.sub.3              H                 H    H         C.sub.6 H.sub.5 --                                H    H         --OCF.sub.3       H              1 #STR85##        H    H              2 #STR86##        H    3,4-OCH.sub.2 O--       H    H              8 #STR87##        H    H              9 #STR88##        H    R.sub.1 and R.sub.2, together with the                            H    carbon atoms to which they are    attached form a benzene ring    H         Cl                 H.    ______________________________________


7. A compound of claim 1 selected from the group consistingof:2'-benzyl-5'-methyl-spiro cyclopentane-1',7' (8'H)- 3'H!-imidazo2,1-b!purin!-4'-(5'H)-one; 2'-benzyl-5,7,7-trimethyl-3H-imidazo2,1-b!purin-4-(5H)-one;(+)-2-benzyl-7,8-dihydro-5-methyl-7-(1-methylethyl)-1H-imidazo2,1-b!-purin-4(5H)-one; (+,-)-6a, 7, 8, 9, 9a, 10, 11,11a-octahydro-5-methyl-2-(3,4-methylene-dioxyphenylmethyl)-3H-pentalen6a, 1:4,5!imidazo 2,1-b!purin-4(5H)-one; and (+)-cis-6a, 7, 9,9a-tetrahydro-5-methyl-2- 4-(trifluoromethyl)-phenylmethyl!-3H-furo 3',4':4,5!imidazo 2,1-b!purin-4(5H)-one.
 8. A pharmaceutical compositioncomprising an effective amount of a compound of claim 1 in apharmaceutically acceptable carrier.
 9. A method of treatinghypertension, angina, bronchoconstriction, restenosis post angioplasty,atherosclerosis, ischemia, peripheral vascular diseases, or diseasesbenefitting from platelet inhibition, or for maintaining guanosine3':5'-cyclic monophosphate (cGMP) levels, comprising administering aneffective amount of a compound of claim 1 to a mammal in need of suchtreatment.